Purine inhibitors of cyclin dependent kinase 2 &amp; IkBa

ABSTRACT

A 2,6,9-trisubstituted purine composition that is useful for inhibiting cell proliferative disorders and as an antifungal agent.

BACKGROUND OF THE INVENTION

[0001] This is a continuation-in-part of U.S. patent application Ser.No. ______ , filed on Jan. 29, 1999, which claims priority to PCTApplication No. PCT/US97/13386, filed on Aug. 1, 1997 which in turn is acontinuation-in-part of co-pending U.S. patent application Ser. No.08/692,012 filed Aug. 2, 1996.

[0002] (1) Field of the Invention

[0003] This invention concerns 2,6,9-trisubstituted purines that havebeen discovered to be selective inhibitors of cell cycle kinases and, assuch, the compounds are inhibitors of cell proliferation. The2,6,9-trisubstituted purines are useful in for example in—treatingautoimmune diseases, e.g. rheumatoid arthritis, lupus, type I diabetes,multiple sclerosis, etc., in treating cancer, cardiovascular disease,such as restenosis, host vs graft disease, gout, polycystic kidneydisease and other proliferative diseases whose pathogenesis involvesabnormal cell proliferation.

[0004] This invention also concerns 2,6,9-trisubstituted purines thathave been discovered to be potent and specific inhibitors of IκB-αkinase which prevents signal induced NF-κB activation and cytokinesynthesis in vitro and in vivo. Such inhibitors are expected to inhibitthe synthesis of cytokines and adhesion proteins whose synthesis istranscriptionally regulated by NF-κB. Proinflammatory cytokines such as1L-1, 1L-6, TNF and adhesion proteins (e.g. ICAM, VCAM and selections)belong to this class of molecules and have been implicated in thepathogenesis of inflammatory diseases. Thus a potent inhibitor of IκB-αkinase is useful in the clinical management of diseases where NF-κBactivation is required for disease induction.

[0005] (2) Description of the Art

[0006] In the past few years, advances in molecular and cellular biologyhave contributed to our understanding of the mechanisms of cellproliferation and of specific events that occur during progression ofcells through mitosis. E.g., “Progress in Cell Cycle Research” Vol 1,Eds. L. Meijer, S. Guidet and H. Y. L. Tung; Plenum Press, New York,1995. These studies have shown that progression through the cell cycleis controlled by a family of serine/threonine kinases called cyclindependent kinases. These enzymes contain (a) a catalytic protein calledcyclin dependent kinase (CDK) that uses ATP as a substrate and (b) aregulatory protein called cyclin. Different cyclin-CDK combinationscontrol events such as growth, DNA replication and cell division. Onekey member of the CDK family of enzymes is CDK2. CDK2 activity has beenshown to be essential for mammalian cell cycle progression at the G1/Sboundary. Microinjection of antibodies directed against CDK2 blocks theprogression of human diploid fibroblasts into the S phase of the cellcycle. Expression of a CDK2 dominant negative mutant in humanosteosarcoma cells has a similar effect. Together, these studiesindicate that inhibition of cellular CDK2 activity will preventprogression of cells through the mitotic cycle and induce growth arrestprior to the S phase. Consistent with this view, in vitro studies witholomoucine (2-(hydroxyethylamino)-6-benzylamino -9-methylpurine), haveshown that it is a specific inhibitor of CDK2 with an IC₅₀ ofapproximately 2.1 μg/ml J. Vesely, et al.; Eur. J.Biochem 224, 771-786(1994), L. Meijer “Chemical Inhibitors of Cyclin-Dependent Kinases” pp351-356 in “Progress in Cell Cycle Research” Vol 1, Eds. L. Meijer, S.Guidet and H. Y. L. Tung; Plenum Press, New York, 1995. In vivo studiesusing mammalian cells in culture have shown that olomoucine inhibitscell proliferation at an approximate concentration of 50 μg/ml.

[0007] In this invention, we have developed several compounds whosebiological activity is considerably more potent than olomoucine. In vivostudies using mammalian cells indicate that some of the disclosedcompounds inhibit cell proliferation at concentrations that aresignificantly lower than olomoucine.

[0008] Recently an IκB-α kinase activity has been described in thecytoplasm of stimulated human umbilical vein endothelial cells (Bennettet al (1996) J. Biol.Chem 271, 19680-19688). Some of the compounds ofthis invention have been identified as potent and specific inhibitors ofIκB-α kinase which prevents signal induced NF-κB activation and cytokinesynthesis in vitro and in vivo. The activation of the heterodimerictranscription factor NF-κB is a complex process. In unstimulated cells,the NF-κB (p50/p65) heterodimer is located in the cytosol where it iscomplexed with an inhibitory subunit IκB-α, IκB-α, binds to NF-κB thusmasking its nuclear localization signal and preventing translocation tothe nucleus. Upon stimulation of cells with a variety of signals (e.g.lipopolysaccharide) IκB-α is rapidly phosphorylated, uniquitinated anddegraded by the proteasome. Degradation of IκB-α, allows thetranslocation of NF-κB to the nucleus where it activates transcriptionof a number of inflammatory response genes.

[0009] These observations suggest that IκB-α kinase is an attractivetarget for the identification of inhibitors that may be useful in thetreatment of inflammatory diseases where NF-κB activation is requiredfor disease induction.

SUMMARY OF THE INVENTION

[0010] It is an object of this invention to provide 2,6,9-trisubstitutedpurine compounds, which inhibit the cyclin dependent kinase 2.

[0011] It is another object of this invention to provide2,6,9-trisubstituted purine compounds which are useful for inhibitingcell proliferation.

[0012] This invention also constitutes a pharmaceutical composition,which comprises a 2,6,9-trisubstituted purine compound and apharmaceutically acceptable carrier.

[0013] This invention further constitutes a method for inhibiting cellproliferation, which comprises administering to a mammal in need thereofan effective amount of a 2,6,9-trisubstituted purine compound.

[0014] In one embodiment, this invention is A 2,6,9-trisubstitutedpurine composition of matter having the following formula:

[0015] wherein R₁ is halogen or R′₁-X wherein X═NH, O, S, S(O₂). In thecomposition, R′₁ is alkyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, and alkynyl, each having one to 20 carbonatoms, which alkyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, CF₃, heteroaryl, heterocyclyl, R²², SR²⁰,S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹, SO₂NR²⁰CONR²⁰R²³,SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰ CONR²⁰R²³,N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³, OCONR²⁰SO₂R²¹,OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ and COR²⁰. Also in thecomposition, R₂ is a hydrogen or hydrocarbon selected from the groupalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, aryl,heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³,SO₂NR²⁰COR²¹, SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹,NR^(°)CO₂R²¹, NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰,OCONR²⁰R²³, OCONR²⁰SO₂R²¹, OCNR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³CONR²⁰SO₂R²¹and COR²⁰. Further, in the compositions, R₃ is a halogen, hydroxyl,thio, alkoxy, alkylthio, alkyl, —NR₄R₅ or a component having theformula:

[0016] where m=1-3, n=1-3, o=1,3, y=carbonyl, —NR₄R₅, hydroxyl, thiol,alkoxy, alkylthiol;

[0017] R₄ and R₅ are each independently hydrogen, OR₂₀, NR₂₀R₂₃, or ahydrocarbon selected from the group including alkyl, acyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, eachhaving one to 20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹,SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³,OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ andCOR²⁰;

[0018] R²⁰ is a member selected from the group consisting of H, C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroarylamide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl;

[0019] R²¹ is a member selected from the group consisting of C₁₋₅ alkyl,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, whichalkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl areoptionally substituted with 1 to 3 substituents independently selectedfrom the group of halo, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰,SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂ NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OR², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, andOCON(R²⁰)₂, and each optional heteroaryl, aryl, and heterocyclylsubstituent is optionally substituted with halo, alkyl, CF₃, amino,mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR²²,NR²⁰S₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR^(°)CON(R²⁰)₂, OC(O)R²⁰,OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

[0020] R² is a member selected from the group consisting of C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, whichalkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroarylamide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl; and

[0021] R²³ is R²¹ or H.

[0022] There are some limitations to the scope of the compositions ofthis invention. When Y is carbonyl, Y and R′₄ together may be a singleoxygen atom, R₄″ and R₅″ together may be a single oxygen atom, R⁴′″ andR₅′″ may together be a single oxygen atom. When R₃ is2-hydroxyethylamino and R₂ is methyl, R₁′-X is not amino,3-methyl-2-butenylamino, benzylamino, or m-hydroxybenzylamino when R₃ isnot 2-hydroxyethylamino. When R₂ is isopropyl, R₁′-X is not benzylamino,m-hydroxybenzylamino, or 3-methylbutylamino. When R₃ is2-hydroxyethylamino and R₂ is 2-hydroxyethyl, R₁′-X is not benzylaminoand when R₃ is selected from the group consisting of2-methyl-2-hydroxypropylamino, and 2-dimethylaminoethylamino, and whenR₂ is methyl, then R₁′-X is not benzylamino

[0023] In another embodiment, this invention is a method for inhibitingcell proliferation in mammals comprising administering a therapeuticallyeffective amount of the composition of claim 1 to the mammal. The methodis useful for treating cell proliferation disorders such as rheumatoidarthritis, lupus, type I diabetes, multiple sclerosis, cancer,restenosis, host graft disease, and gout.

[0024] In yet another embodiment, this invention is a pharmaceuticalcomposition of matter comprising the composition above in an admixturewith one or more pharmaceutical excipients.

[0025] In still another embodiment, this invention is a compositionuseful for treating fungal infections (fungi) in humans, animals, and inplants.

DESCRIPTION OF THE FIGURE

[0026]FIG. 1 is a plot of the mean neointimal area of a rat carotidartery treated with a saline vehicle and treated with compound 3prepared according to Example 2 wherein the unshaded bar represents theuntreated section of the carotid artery and the shaded bar representsthe treated section of the carotid artery.

DESCRIPTION OF THE CURRENT EMBODIMENT

[0027] The present invention relates to a 2,6,9-trisubstituted purinecompound having the following formulas:

[0028] where:

[0029] R₁ is halogen or R′₁−X wherein X═NH, O, S, S(O₂).

[0030] R′₁ is alkyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, and alkynyl, each having one to 20 carbonatoms, which alkyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, CF₃, heteroaryl, heterocyclyl, R²², SR²⁰,S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹, SO₂NR²⁰CONR²⁰R²³,SO₂NR²⁰CO₂R²¹, NR²⁰NR²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³,N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³, OCONR²⁰S₂R²¹,OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ and COR²⁰;

[0031] R₂ is a hydrogen or hydrocarbon selected from the group alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl,andalkynyl, each having one to 20 carbon atoms, which alkyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl,and alkynyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹,SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³,OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ andCOR²⁰;

[0032] R₃ is a halogen, hydroxyl, thio, alkoxy, alkylthio, alkyl, —NR₄R₅or a component having the formula:

[0033] where m=1-3, n=1-3, o=1,3, y=carbonyl, —NR₄R₅, hydroxyl, thiol,alkoxy, alkylthiol;

[0034] R⁴ and R₅ are each independently hydrogen, OR₂₀, NR₂₀R₂₃, or ahydrocarbon selected from the group including alkyl, acyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, eachhaving one to 20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹,SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³,OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ andCOR²⁰; with the proviso that when Y is carbonyl, Y and R′₄ together maybe a single oxygen atom, R₄″ and R₅″ together may be a single oxygenatom, R₄′″ and R₅′″ may together be a single oxygen atom, and whereinwhen R₃ is 2-hydroxyethylamino and R₂ is methyl, R₁′-X is not amino,3-methyl-2-butenylamino, benzylamino, or m-hydroxybenzylamino, when R₃is not 2-hydroxyethylamino, when R₂ is isopropyl, R₁′-X is notbenzylamino, m-hydroxybenzylamino, or 3-methylbutylamino, when R₃ is2-hydroxyethylamino and R₂ is 2-hydroxyethyl, R₁′-X is not benzylaminoand when R₃ is selected from the group consisting of2-methyl-2-hydroxypropylamino, and 2-dimethylaminoethylamino, and whenR₂ is methyl, then R₁′-X is not benzylamino.

[0035] In the compositions, R²⁰ is a member selected from the groupconsisting of H, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to3 substituents independently selected from halo, alkyl, mono- ordialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃,aryl, and heteroaryl.

[0036] Also in the compositions, R²¹ is a member selected from the groupconsisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl,aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl,and heteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from the group of halo, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂ NR²⁰COR²²,NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OR²⁰, OCONR²⁰SO₂R²², OC(O)R²⁰,C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, and each optional heteroaryl, aryl,and heterocyclyl substituent is optionally substituted with halo, alkyl,CF₃, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide,NCOR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰,OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰.

[0037] In the compositions, R²² is a member selected from the groupconsisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl,aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl,and heteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl,and R²³ is R²¹ or H.

[0038] R′₁ is preferably an aryl, substituted aryl, each having 6 carbonatoms wherein substitution includes optional substitution with from 1 to2 substituents independently selected from the group consisting of halo,CF₃, aryl, R²², NR²⁰R²³, NR²⁰COR²¹, OR²⁰, CN; an aralkyl, substitutedaralkyl, each having 6-8 carbon atoms wherein substitution includesoptional substitution with from 1 to 2 substituents independentlyselected from the group consisting of halo, CF₃, aryl, R²², NR²⁰R²³,NR²⁰COR²¹, OR²⁰, CN; —CH₂-phenyl wherein the phenyl ring is optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, CF₃, R²², OR²⁰, CN; substitutedpyridylalkyl; unsubstituted pyridylalkyl; pyridyl; substituted pyridyl;and benzyl substituted with a halogen, alkoxy, phenyl, pyridyl or nitrogroup. In some compositions, R′₁ is preferably CH₂ -aryl or CH₂-substituted aryl. Most preferably, R₁′ is selected from3-methylthiophenyl, 4-methylthiophenyl, 4-phenylbenzyl, 4-methoxybenzyl,4-biphenyl, 3-methoxybenzyl, 4-(2-thienyl)benzyl,4-(4-methyl)phenylbenzyl, 4-(4-trifluoromethyl)phenylbenzyl,4-(4-nitrilo)phenylbenzyl, 4-(2-pyridinyl)benzyl, piperonyl,3-methoxbenzyl, 4-chlorobenzyl, and 4-nitrobenzyl.

[0039] R₂ is preferably hydrogen or a hydrocarbon selected from thegroup substituted lower alkyl, cycloalkyl, substituted cycloalkyl eachhaving one to 6 carbon atoms wherein substitution includes optionalsubstitution with from 1 to 2 substituents independently selected fromthe group consisting of halo, R²², NR²⁰R²³, OR²⁰; substituted alkyl,cycloalkyl, substituted cycloalkyl each having one to 6 carbon atomswherein substitution includes optional substitution with from I to 2substituents independently selected from the group consisting of halo,R²², NR²⁰R²³, and OR²⁰. More preferably, R₂ is isopropyl.

[0040] R₃ is preferably —NR₄R₅ wherein R₄ and R₅ are each selected fromthe group consisting of hydrogen, alkyl, heterocyclyl, acyl, aryl,heteroaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, eachhaving one to 20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroarylalkyl, are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹,SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³.NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, CONR²⁰R²³, and COR₂₀. In somecompositions, R₄ and R₅ are preferably each H, —CH₂CH₂OH , —CHR′CH₂OH,or —CH₂CHR′OH, —CH₂CH₂NH₂, CHR′CH₂NH₂, —CH₂CHR′NH₂ wherein R′ ishydrogen or alkyl having from I to 6 carbon atoms. R²⁰ is preferably amember selected from the group consisting of H, C₁₋₈ alkyl.

[0041] R²¹ is preferably a member selected from the group consisting ofC₁₋₃ alkyl, which alkyl is optionally substituted with 1 to 2substituents independently selected from the group of halo, CF₃, CN,OR²⁰, SR²⁰, N(R²⁰)₂.

[0042] R²² is preferably a member selected from the group consisting ofC₁₋₃ alkyl, aryl, heteroaryl which alkyl, aryl, and heteroaryl areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, alkyl, mono- or dialkylamino, alkyl or aryl, CN, O—C₁₋₆alkyl, and CF₃.

[0043] Preferred 2,6,9-trisubstuted purine compositions of thisinvention include2-{(2-hydroxyethyl)[9-(methylethyl)-6-({[4-(trifluoromethyl)phenyl]methyl}amino)purin-2-yl]amino}ethan-1-ol,{((2S)oxolan-2-yl)methyl](6-{[(4-fluorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,[((2R)oxolan-2-yl)methyl](6-{[(4-fluorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,(2-aminoethyl)(6-{[3,5-dichlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,(2-aminoethyl)[6-({[4-chloro-3-(trifluoromethyl)phenyl]methyl}amino)-9-(methylethyl)purin-2-yl]amine,[-[(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]-3-methylbutanamide,(2-amino-2-methylpropyl)(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,3-(2-[bis(2-hydroxyethyl)amino]-6-{[4-chlorophenyl)methyl]amino}purin-9-yl)butan-2-one,2-[(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]-3-methylbutan-1-ol,4-[({2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}amino)methyl]benzenesulfonamide,2-[(2-hydroxyethyl)(6-{[(4-methoxyphenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]ethan-1-ol, 2-((2-hydroxyethyl){9-(methylethyl)-6-[(4-phenylphenyl)amino]purin-2-yl}amino)ethan- 1-ol,{2-[(2-amino-2-propyl)amino]-9-(methylethyl)purin-6-yl}[(4-hlorophenyl)methyl]amine,{2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]amine,{2-[(2-aminopropyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]amineand2-[(2-aminoethyl)(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]ethan-1-ol.

[0044] There are some limitations to the scope of R₁, R₁′, R₂ and R₃. Asmentioned above, when R₃ is 2-hydroxyethylamino and R₂ is methyl, R₁′-Xcannot be amino, 3-methyl-2-butenylamino, benzylamino, orm-hydroxybenzyl-amino. When R₃ is 2-hydroxyethylamino and R₂ isisopropyl, R₁′-X cannot be benzylamino, m-hydroxybenzylamino, or3-methylbutylamino. When R ₃ is 2-hydroxyethylamino and R ₂ is2-hydroxyethyl, R₁′-X cannot be benzylamino. When R₃ is2-propanol-2-methylamino or 2-dimethylaminoethylamino and R₂ is methyl,R₁′-X cannot be benzylamino.

[0045] The following are definitions for certain terms used herein.

[0046] “Halo” or “Halogen”—alone or in combination means all halogens,that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).

[0047] “Hydroxyl” refers to the group —OH.

[0048] “Thiol” or “mercapto” refers to the group —SH.

[0049] “Alkyl” —alone or in combination means an alkane-derived radicalcontaining from 1 to 20, preferably 1 to 15, carbon atoms (unlessspecifically defined). It is a straight chain alkyl, branched alkyl orcycloalkyl. Preferably, straight or branched alkyl groups containingfrom 1-15, more preferably 1 to 8, even more preferably 1-6, yet morepreferably 1-4 and most preferably 1-2, carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “loweralkyl” is used herein to describe the straight chain alkyl groupsdescribed immediately above. Preferably, cycloalkyl groups aremonocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclohexyl, adamantyl and the like. Alkyl also includes a straight chainor branched alkyl group that contains or is interrupted by a cycloalkylportion. The straight chain or branched alkyl group is attached at anyavailable point to produce a stable compound. Examples of this include,but are not limited to, 4-(isopropyl)-cyclohexylethyl or2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chainalkyl, branched alkyl, or cycloalkyl group defined previously,independently substituted with 1 to 3 groups or substituents of halo,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,aryloxy, heteroaryloxy, amino optionally mono- or di-substituted withalkyl, aryl or heteroaryl groups, amidino, urea optionally substitutedwith alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyloptionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroarylgroups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0050] “Alkenyl” —alone or in combination means a straight, branched, orcyclic hydrocarbon containing 2-20, preferably 2-17, more preferably2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and atleast one, preferably 1-3, more preferably 1-2, most preferably one,carbon to carbon double bond. In the case of a cycloalkyl group,conjugation of more than one carbon to carbon double bond is not such asto confer aromaticity to the ring. Carbon to carbon double bonds may beeither contained within a cycloalkyl portion, with the exception ofcyclopropyl, or within a straight chain or branched portion. Examples ofalkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl isthe straight chain alkenyl, branched alkenyl or cycloalkenyl groupdefined previously, independently substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, or the like attached at any available point toproduce a stable compound.

[0051] “Alkynyl” —alone or in combination means a straight or branchedhydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms containing atleast one, preferably one, carbon to carbon triple bond. Examples ofalkynyl groups include ethynyl, propynyl, butynyl and the like. Asubstituted alkynyl refers to the straight chain alkynyl or branchedalkenyl defined previously, independently substituted with 1 to 3 groupsor substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, or the like attached at any available point toproduce a stable compound.

[0052] “Alkyl alkenyl” refers to a group —R—CR′═CR′″ R″″, where R islower alkyl, or substituted lower alkyl, R′, R′″, R″″ may independentlybe hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl,substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0053] “Alkyl alkynyl” refers to a groups —RC≡CR′ where R is lower alkylor substituted lower alkyl, R′ is hydrogen, lower alkyl, substitutedlower alkyl, acyl, aryl, substituted aryl, hetaryl, or substitutedhetaryl as defined below.

[0054] “Alkoxy” denotes the group —OR, where R is lower alkyl,substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl as defined.

[0055] “Alkylthio” denotes the group —SR, —S(O)_(n=1-2)—R, where R islower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl orsubstituted aralkyl as defined herein.

[0056] “Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkylsubstituted lower alkyl, aryl, substituted aryl and the like as definedherein.

[0057] “Aryloxy” denotes groups —OAr, where Ar is an aryl, substitutedaryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0058] “Amino” denotes the group NRR′, where R and R′ may independentlyby hydrogen, lower alkyl, substituted lower alkyl, aryl, substitutedaryl, hetaryl, or substituted hetaryl as defined herein or acyl.

[0059] “Amido” denotes the group —C(O)NRR′, where R and R′ mayindependently by hydrogen, lower alkyl, substituted lower alkyl, aryl,substituted aryl, hetaryl, substituted hetaryl as defined herein.

[0060] “Carboxyl” denotes the group —C(O)OR, where R is hydrogen, loweralkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, andsubstituted hetaryl as defined herein.

[0061] “Aryl” —alone or in combination means phenyl or naphthyloptionally carbocyclic fused with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members and/or optionally substituted with 1 to 3groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0062] “Substituted aryl” refers to aryl optionally substituted with oneor more functional groups, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0063] “Heterocycle” refers to a saturated, unsaturated, or aromaticcarbocyclic group having a single ring (e.g., morpholino, pyridyl orfuryl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl,quinolinyl, indolizinyl or benzo[b]thienyl) and having at least onehetero atom, such as N, O or S, within the ring, which can optionally beunsubstituted or substituted with, e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0064] “Heteroaryl” —alone or in combination means a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group O, S, and N, and optionally substituted with 1to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, amino sulfonyl optionally N-mono- orN,N-di- sub stituted with alkyl, aryl or heteroaryl groups,alkylsulfonylarnino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable aromatic ring is retained. Examples ofheteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and thelike. A substituted heteroaryl contains a substituent attached at anavailable carbon or nitrogen to produce a stable compound.

[0065] “Heterocyclyl” —alone or in combination means a non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally benzo fused or fused heteroaryl of 5-6 ring members and/orare optionally substituted as in the case of cycloalkyl. Heterocycyl isalso intended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. The point of attachment is at acarbon or nitrogen atom. Examples of heterocyclyl groups aretetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl,piperazinyl, dihydrobenzoflryl, dihydroindolyl, and the like. Asubstituted hetercyclyl contains a substituent nitrogen attached at anavailable carbon or nitrogen to produce a stable compound.

[0066] “Substituted heteroaryl” refers to a heterocycle optionally monoor poly substituted with one or more functional groups, e.g., halogen,lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0067] “Aralkyl” refers to the group —R—Ar where Ar is an aryl group andR is lower alkyl or substituted lower alkyl group. Aryl groups canoptionally be unsubstituted or substituted with, e.g., halogen, loweralkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl,aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0068] “Heteroalkyl” refers to the group —R—Het where Het is aheterocycle group and R is a lower alkyl group. Heteroalkyl groups canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl,aryloxy, heterocycle, substituted heterocycle, hetaryl, substitutedhetaryl, nitro, cyano, thiol, sulfamido and the like.

[0069] “Heteroarylalkyl” refers to the group —R—HetAr where HetAr is anheteroaryl group and R lower alkyl or substituted lower alkyl.Heteroarylalkyl groups can optionally be unsubstituted or substitutedwith, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy,alkylthio, acetylene, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0070] “Cycloalkyl” refers to a divalent cyclic or polycyclic alkylgroup containing 3 to 15 carbon atoms.

[0071] “Substituted cycloalkyl” refers to a cycloalkyl group comprisingone or more substituents with, e.g., halogen, lower alkyl, substitutedlower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0072] “Cycloheteroalkyl” refers to a cycloalkyl group wherein one ormore of the ring carbon atoms is replaced with a heteroatom (e.g., N, O,S or P).

[0073] “Substituted cycloheteroalkyl” refers to a cycloheteroalkyl groupas herein defined which contains one or more substituents, such ashalogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido,carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle,hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and thelike.

[0074] “Alkyl cycloalkyl” denotes the group —R-cycloalkyl wherecycloalkyl is a cycloalkyl group and R is a lower alkyl or substitutedlower alkyl. Cycloalkyl groups can optionally be unsubstituted orsubstituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio,acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0075] “Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkylwhere R is a lower alkyl or substituted lower alkyl. Cycloheteroalkylgroups can optionally be unsubstituted or substituted with e.g. halogen,lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0076] “Pharmacologically acceptable salt” —a salt prepared byconventional means, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. When compounds of formula I-IE include an acidicfunction such as a carboxy group, then suitable pharmaceuticallyacceptable cation pairs for the carboxy group are well known to thoseskilled in the art and include alkaline, alkaline earth, ammonium,quaternary ammonium cations and the like. For additional examples of thetypes of compounds that are “pharmacologically acceptable salts,” seeBerge et al, J Pharm. Sci. 66, 1 (1977).

[0077] If the final 2,6,9-trisubstituted purine compound of thisinvention contains a basic group, then an acid addition salt of thecomposition may be prepared. Acid addition salts of the compounds ofthis invention are prepared in a standard manner in a suitable solventfrom the parent compound and an excess of acid, such as, but not limitedto, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic,succinic, citric or methanesulfonic. The hydrochloric salt form isespecially useful.

[0078] If the final 2,6,9-trisubstituted purine compound contains anacidic group, then cationic salts of the composition may be prepared.Typically the acidic parent compound is a treated with an excess of analkaline reagent, such as, but not limited to, hydroxide, carbonate oralkoxide, containing the appropriate cation such as but not limited to,Na⁺, K⁺, Ca⁺² and NH₄ ⁺. Certain of the compounds form inner salts orzwitterions which are also acceptable.

[0079] The compounds of this invention are useful in inhibiting cellproliferation in mammals including humans. The 2,6,9-trisubstitutedpurines are useful in for example in treating autoimmune diseases, e.g.rheumatoid arthritis, lupus, type I diabetes, multiple sclerosis,cancer, cardiovascular disease such as restenosis following balloonangioplasty and atherectomy, restensosis following vascular modifyingsurgical procedures, host vs graft disease, gout, polycystic kidneydisease and other proliferative diseases whose pathogenesis involvesabnormal cell proliferation. In particular, the compositions of thisinvention are useful in treating cancers including cancers includinglymphoyd neoplasm, cancer of the colon, breast cancer, ovarian cancer,pancreatic cancer, and cancers derived of endotherical cells.

[0080] The method of treatment comprises the administrationparenterally, and orally, of an effective quantity of the chosencompound of this invention, preferably dispersed in a pharmaceuticalcarrier. Therapeutically useful amounts of the composition of thisinvention will generally range from about 0.01 to about 100 mg/kg, butwill be readily determined by one skilled in the art depending upon theroute of administration, and the age and condition of the patient.Therapeutically useful amounts of the composition of this invention maybe administered from one to ten times daily or more for acute or chronicdisease. No unacceptable toxicological effects are expected whencompounds of the invention are administered in accordance with thepresent invention.

[0081] The compounds of this invention are also useful asantiinflammatory and antifungal agents. As such, the compositions ofthis invention are useful for treating antiinflammatory and fungalinfections in humans, animals, and fungal infections in plants.

[0082] Pharmaceutical compositions including the compounds of thisinvention, and/or derivatives thereof, may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. If used in liquid formthe compositions of this invention are preferably incorporated into abuffered, isotonic, aqueous solution. Examples of suitable diluents arenormal isotonic saline solution, standard 5% dextrose in water andbuffered sodium or ammonium acetate solution. Such liquid formulationsare suitable for parenteral administration, but may also be used fororal administration.

[0083] It may be desirable to add excipients such aspolyvinylpyrrolidinone, gelatin, hydroxycellulose, acaia, polyethyleneglycol, mannitol, sodium chloride, sodium citrate or any other excipientknown to one of skill in the art to pharmaceutical compositionsincluding compounds of this invention. Alternatively, the pharmaceuticalcompounds may be encapsulated, tableted or prepared in an emulsion orsyrup for oral administration. Pharmaceutically acceptable solid orliquid carriers may be added to enhance or stabilize the composition, orto facilitate preparation of the composition. Liquid carriers include,but are not limited to syrup, peanut oil, olive oil, glycerin, saline,alcohols and water. Solid carriers include, but are not limited to,starch, lactose, calcium sulfate, dihydrate, teffa alba, magnesiumstearate or stearic acid, talc, pectin, acacia, agar or gelatin. Thecarrier may also include a sustained release material such as, but notlimited to, glyceryl monostearate or glyceryl distearate, alone or witha wax. The amount of solid carrier varies but, preferably, will bebetween about 20 mg to about 1 gram per dosage unit.

[0084] The pharmaceutical dosages are made using conventional techniquessuch as, but not limited to, milling, mixing, granulation, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly or filled into a soft gelatin capsule.

[0085] The Examples which follow serve to illustrate this invention. TheExamples are intended to in no way limit the scope of this invention,but are provided to show how to make and use the compounds of thisinvention. In the Examples, all temperatures are in degrees Centigrade.RT indicates room temperature.

EXAMPLE 1

[0086] The compounds of this invention are prepared by conventionalmethods of organic chemistry. The reaction sequence outlined in thesynthesis scheme below is a general method useful for the synthesis ofcompounds of this invention. 2,6-dichloropurine is dissolved in butanoland the appropriate R₁ amine is added. After heating for several hours,the reaction mixture is cooled, and the compound 1 is obtained. Tocompound 1, is added, sodium hydride followed by R₂, and compound 2 isisolated. To compound 2, R₃ is added in solution withN-methylpyrrolidinone. The mixture is heated for an appropriate periodfollowed by purification leading to the desired compound.

[0087] The following compound was prepared according to the methodabove.

Preparation of 2-chloro-6-(4-methoxybenzylamino) purine (1).

[0088] The 2,6-dichloropurine (4.06 g, 21.5 mmol) was suspended inn-butanol (150 ml) and the 4-methoxybenzylamine was added (3.4 ml, 26mmol). The solution turned clear and then cloudy a few minutes later.The solution was heated at 120° C. for 2 hr and then cooled. Then-butanol was evaporated followed by suspension of the residue in waterand diethyl ether mixture. A solution of 2N NaOH (1.3 ml, 26 mmol) wasadded and the solution stirred for 10 min before filtration. Thefiltered precipitate was washed with water and a small portion of etherand then dried under vacuum. The residual liquor was left overnight andmore crystals were collected the next day and washed with diethyl ether.

Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2)

[0089] 2-chloro-6-(4-methoxybenzylamino) purine was suspended in dry DMF(5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06mmol). The suspension was stirred for 30 min over which time it became aclear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was addedover 5 min and the resultant solution stirred for 2 days. Water wasadded and the solution and extracted with ethyl acetate. The organiclayer was evaporated to give the product isopropyl purine.

Preparation of2-diethanolamino-6-(4-methoxybenzylamino)-9-isopropylpurine, (3).

[0090] The purine (1.65 g, 4.98 mmol) was dissolved in DMSO₍12 mL) anddiethanolamine (4 mL) and then heated at 140° C. for 2-3 days and thenat 160° C. for 1 day. The solution was cooled and water saturatedbutanol was added (100 mL). The solution was then washed with water(3×50 mL), before being evaporated to give a brown oil. The residue waschromatographed over silica gel eluting with ethyl acetate, followed by3% methanol in ethyl acetate to give the product. ¹H-NMR(δCDCl3):7.29(br s 1H), 7.25(d, 2H), 6.94(br s. 1H), 6.83(d. 2H), 5.43(br s.<2H),4.63(br s. 2H), 4.53(m 1H), 3.86(t. 4H), 3.76(m, 7H), 1.47(d 6H).

[0091] Table 1 identifies compounds of this invention that were preparedaccording to the synthesis method set forth in this Example. TABLE 1Compounds Prepared By The Method of Example 1 R₁X R₂ R₃(4-methoxyphenyl)methylamino 3-cyanopropyl Cl(4-methoxyphenyl)methylamino 3-chloropropyl Cl(4-methoxyphenyl)methylamino benzyl Cl (4-methoxyphenyl)methylamino(4-methylcarboxyphenyl)methyl Cl (4-methoxyphenyl)methylamino2-(N-phtyhaloyl)ethyl Cl (4-methoxyphenyl)methylamino isopropylEthanolamine (4-methoxyphenyl)methylamino isopropyl Diethanolamine(4-methoxyphenyl)methylamino 3-methylbutyl Cl(4-methoxyphenyl)methylamino 2-methylbutyl Cl(4-methoxyphenyl)methylamino cyclopentyl Cl (4-methoxyphenyl)methylamino(3-nitrophenyl)methyl Cl (4-methoxyphenyl)methylamino(4-nitrophenyl)methyl Cl (4-methoxyphenyl)methylamino ethyl Cl(4-methoxyphenyl)methylamino propyl Cl (4-methoxyphenyl)methylamino(3-methylphenyl)methyl Cl (4-methoxyphenyl)methylamino(4-methylphenyl)methyl Cl heptylamino H Cl N-benzyl-N-hydroxylamino H Clpropylamino H Cl noradamantylamino H Cl cyclobutylamino H Cl3-methoxypropylamino H Cl 2-methoxyethylamino H Cl cyclopentylamino H Cl1-hydroxy-2-methyl-2-propylamino H Cl (N-1-benzylpiperidinyl)-4-amino HCl heptylamino Methyl Cl N-benzyl-N-hydroxylamino Methyl Cl propylaminoMethyl Cl noradamantylamino Methyl Cl cyclobutylamino Methyl Cl3-methoxypropylamino Methyl Cl 2-methoxyethylamino Methyl Clcyclopentylamino Methyl Cl 1-hydroxy-2-methyl-2-propylamino Methyl Cl(N-1-benzylpiperidinyl)-4-amino Methyl Cl(2,4-dimethoxyphenyl)methylamino Methyl Cl (2-methoxyphenyl)methylaminoH Cl (2-pryidinyl)methylamino H Cl (3,4-dimethoxyphenyl)ethylamino H Cl(3-pyridinyl)methylamino H Cl (4-pyridinyl)methylamino H Cl6-hydroxy-1-hexylamino H Cl phenethylamino H Cl (2-benzothiazolyl)aminoH Cl (2,4-dimethoxyphenyl)methylamino H Cl (2-methoxyphenyl)methylaminoMethyl Cl (2-pyridinyl)methylamino Methyl Cl(3,4-dimethoxyphenyl)ethylamino Methyl Cl (4-methoxyphenyl)methylaminoMethyl Cl (3-pyridinyl)methylamino isopropyl 2-aminoethylamino(4-pyridinyl)methylamino H Cl 1-hydroxy-6-hexylamino H Cl phenethylaminoH Cl (2-benzothiazolyl)amino H Cl (4-methoxyphenyl)methylamino H Cl3-phenyl-1-propylamino isopropyl 3-hydroxypyrrolidino (2-indanyl)amino HCl (4-methoxyphenyl)ethylamino H Cl (4-nitrophenyl)methylamino H Cl(2,6-difluorophenyl)methylamino H Cl 3-phenyl-1-propylamino H Cl(2-indanyl)amino Methyl Cl (4-methoxyphenyl)ethylamino Methyl Cl(4-nitrophenyl)methylamino Methyl Cl (2,6-difluorophenyl)methylaminoMethyl Cl cyclopropylmethylamino Methyl Cl 4-(1,2-methylenedioxyphenyl)H Cl methylamino (4- H Cl aminosulfonylphenyl)methylamino(cyclohexanol)-1-methylamino H Cl (2-benzimidazoly)methylamino H Clcyclohexylmethylamino H Cl (4-methoxyphenyl)methylamino H Cl(4-methoxyphenyl)methylamino isopropyl (2-hydroxy-1-hydroxymethyl)ethylamino cyclopropylmethlamino isopropyl3-amino-2-hydroxypropylamino 4-(1,2-methylene- Methyl Cldioxyphenyl)methylamino (4-aminosulfonyl- Methyl Cl phenyl)methylamino(cyclohexanol)-1-methylamino Methyl Cl (2-benzimidazolyl)methylaminoMethyl Cl cyclohexylmethylamino Methyl Cl (3-pyridinyl)methylaminoMethyl Cl (4-pyridinyl)methylamino 2-methylpropyl Cl 6-hydroxyhexylaminocyclopentyl Cl phenethylamino propyl Cl (2-benzothiazolyl)amino ethyl Cl3-phenyl-1-propylamino isopropyl Cl (2-indanyl)amino 2-methylpropyl Cl2-(4-methoxyphenyl)ethylamino cyclopentyl Cl (4-nitrophenyl)methylaminopropyl Cl (2,6-difluorophenyl)methylamino ethyl Cl(4-methoxyphenyl)methylamino isopropyl Cl 3-phenyl-1-propylaminoisopropyl 4-hydroxypiperidino (2-indanyl)amino H Cl2-(4-methoxyphenyl)ethylamino H Cl (4-nitrophenyl)methylamimo H Cl(2,6-difluorophenyl)methylamino H Cl (4-methoxyphenyl)methylamino H Cl(4-methoxyphenyl)methylamino isopropyl N-(2-cyanoethyl)-N-benzylamino3-phyenyl-1-propylamino isopropyl 1-(R,S)-hydroxymethyl-3-methylbutylamino (2-indanyl)amino isopropyl Cl2-(4-Methoxyphenyl)ethylamino isopropyl Cl (4-nitrophenyl)methylaminoisopropyl Cl (2,6-difluorophenyl)methylamino isopropyl Cl(4-methoxyphenyl)methylamino isopropyl Cl (4-methoxyphenyl)methylaminoisopropyl Piperidino (4-methoxyphenyl)methylamino isopropyl3-hydroxypiperidino 3-phenyl-1-propylamino isopropyl1-(S)-hydroxymethyl-2-(4′- imidazolyl)ethylamino (2-indanyl)aminoisopropyl diethanolamino (4-methyoxyphenyl)methylamino isopropyldiethanolamino (4-methyoxyphenyl)methylamino isopropyl2-(S)-hydroxymethylpyrrolidino (4-methyoxyphenyl)methylamino isopropyldiethanolamino (4-methyoxyphenyl)methylamino benzyl morpholino(4-methyoxyphenyl)methylamino 3-methylbutyl diethanolamino(4-methyoxyphenyl)methylamino 2-methylbutyl diethanolamino(4-methyoxyphenyl)methylamino cyclopentyl diethanolamino(4-methyoxyphenyl)methylamino (3-nitrophenyl)methylamimo diethanolamino(4-methyoxyphenyl)methylamino (4-nitrophenyl)methylamino diethanolamino(4-methyoxyphenyl)methylamino ethyl diethanolamino(4-methyoxyphenyl)methylamino propyl diethanolamino(4-methyoxyphenyl)methylamino (3-methylphenyl)methylamimo diethanolaminoheptylamino (4-methylphenyl)methylamino diethanolaminoN-benzyl-N-hydroxyamino Methyl diethanolamino propylamino Methyldiethanolamino noradamantylamino Methyl diethanolamino cyclobutylaminoMethyl diethanolamino 3-methoxypropylamino Methyl diethanolamino2-methoxyethylamino Methyl diethanolamino cyclopentylamino Methyldiethanolamino 1-hydroxy-2-methyl-2-propylamino Methyl diethanolamino4-(1-benzylpiperidinyl)amino Methyl diethanolamino(4-methoxyphenyl)methylamino Methyl diethanolamino(4-methoxyphenyl)methylamino isopropyl diethanolamino(2,4-dimethoxy-phenyl) isopropyl 3-hydroxypyrrolidino methylamino(2-methoxyphenyl)methylamino Methyl 2-(3′indolyl)ethylamino(2-pyridinyl)methylamino Methyl diethanolamino 2-(3,4- Methyldiethanolamino dimethoxyphenyl)ethylamino (3-pyridinyl)methylaminoMethyl diethanolamino (4-pyridinyl)methylamino Methyl diethanolamino6-hydroxy-1-hexylamino Methyl diethanolamino phenethylamino Methyldiethanolamino (2-benzothiazolyl)amino Methyl diethanolamino3-phenyl-1-propylamino Methyl diethanolamino (2-indanyl)amino Methyldiethanolamino 2-(4-methoxyphenyl)ethylamino Methyl diethanolamino(4-nitrophenyl)methylamino Methyl diethanolamino(2,6-difluorophenyl)methylamino Methyl diethanolaminocyclopropylmethylamino Methyl diethanolamino 4-(1,2-methylenedioxy-Methyl diethanolamino phenyl)methylamino (4-aminosulfonylphenyl)- Methyldiethanolamino methylamino (cyclohexanol)-1-methylamimo Methyldiethanolamino (2-benzimidazolyl)methylamino Methyl diethanolaminocyclohexylmethylamino Methyl diethanolamino (3-pyridyl)methylaminoMethyl diethanolamino (4-pyridyl)methylamino 2-methylpropyldiethanolamino 6-hydroxy-1-hexylamino cyclopentyl diethanolamino2-phenethylamino propyl diethanolamino (2-benzothiazolyl)amino ethyldiethanolamino 3-phenyl-1-propylamino isopropyl diethanolamino(2-indanyl)amino 2-methylpropyl diethanolamino2-(4-methoxyphenyl)ethylamino cyclopentyl diethanolamino(4-nitrophenyl)methylamimo propyl diethanolamino(2,6-difluorophenyl)methylamino ethyl diethanolamino(4-methyoxyphenyl)methylamino isopropyl diethanolamino(4-methyoxyphenyl)methylamino isopropyl 1-hydroxymethylcyclopentylamino(4-methyoxyphenyl)methylamino isopropyl 2-(R,S)-hydroxymethylpiperidinocyclopropylmethylamino isopropyl 2,3-dihydroxy-1-propylamino4-(1,2-methylenedioxyphenyl) isopropyl Cl methylamino(4-aminosulfonylphenyl) isopropyl Cl methylamino(cyclohexanol)-1-methylamimo isopropyl Cl (2-benzimidazolyl)aminoisopropyl Cl cyclohexylmethylamino isopropyl Cl 3-phenyl-1-propylaminoisopropyl Cl cyclopropylmethylamino cyclopentyl Cl4-(1,2-methylenedioxyphenyl) isopropyl diethanolamino methylamino(4-methoxyphenyl)methylamino isopropyl diethanolamino(4-methoxyphenyl)methylamino isopropyl diisopropylamino(4-methoxyphenyl)methylamino isopropyl (trans-2-hydroxycyclohexyl)amino(4-methoxyphenyl)methylamino isopropyl 2(R)-(1-hydroxy-3-phenyl)propylamino (4-methoxyphenyl)methylamino isopropyl5-(S)-(2,2-dimethyl-4(S)- phenyldioxalanyl)amino(4-methoxyphenyl)methylamino isopropyl 3-(N-1-imidazolyl)propylamino(4-methoxyphenyl)methylamino isopropyl 4-hydroxyl-4-phenylpiperidino(4-methoxyphenyl)methylamino isopropyl (2-benzylthio-1-hydroxymethyl)ethylamino (4-methoxyphenyl)methylamino isopropylN-methyl-N-(2-hydroxy-2-(3,4- dihydroxyphenyl)ethyl)amino(4-methoxyphenyl)methylamino isopropyl diallylamino(4-methoxyphenyl)methylamino isopropyl Piperazino(4-methoxyphenyl)methylamino isopropyl (+/−)N-methyl-N-(2-hydroxy-2-phenylethyl)amino (4-methoxyphenyl)methylamimo isopropyl (S)-(+)-2-(anilinomethyl)pyrrolidino (4-methoxyphenyl)methylamino isopropyl(+/−)N-(2-propenyl)-N-2-(4- hydroxy-2-methylpentyl)amino(4-methoxyphenyl)methylamino isopropyl N-(2-hydroxyethyl)-N-(3-hydroxypropyl)amino (4-methoxyphenyl)methylamino isopropylDi-N-1-(2-hydroxy-2- methylpentyl)amino (4-methoxyphenyl)methylamimoisopropyl Di-N-2-(3-hydroxybutyl)amino

EXAMPLE 2

[0092] This example describes a method for preparing compounds of thisinvention according to the following general synthesis scheme:

Preparation of {2-chloropurin-6-yl}[(4-chlorophenyl)methyl]amine:

[0093] To a suspension of 15 g (0.0794 mol) of 2,6-dichloropurine in 250mL of absolute ethanol was added 12.7 mL (0.0873 mol) of triethylamineand 10.62 mL (0.0873 mol) of 4-chlorobenzylamine. The mixture wasrefluxed at 80° C. for 16 h (the formation of creamy white precipitatewas observed). The reaction mixture was cooled and the precipitatedproduct was removed by filtration. The precipitate was washed withethanol (350 mL) and dried in high vacuum for 24 h. Product wascharacterized by ¹H-NMR.

Preparation of{2-chloro-9-(methylethyl)purin-6-yl}[4-chlorophenyl)methyl]amine:

[0094] To a solution of 6 g (0.020 mol) of2-chloro-6-(4-chlorophenyl)methylaminopurine in 41 mL of anhydrous DMFwas added 5.64 g (0.041mol) anhydrous. potassium carbonate and 3.41mL,(0.035 mol of 2-iodopropane) and stirred at room temperature for 16h.To the mixture 500 mL of water was added and stirred for 1 h. Theprecipitate was filtered, washed with water (350 mL), and dried invacuum oven at 50° C. for 16 h. The product was obtained as an off whitesolid and characterized by ¹H-NMR.

Preparation of{2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]amine:

[0095] To a solution of 3.36 g (0.01 mol) of{2-chloro-9-(methylethyl)purin-6-yl}[4-chlorophenyl)methyl]amine in 13mL of anhy. 1-methyl-2-pyrrolidinone was added 4.68 mL (0.70 mol) of2-aminoethylamine and the mixture was heated at 140° C. for 24 h. Thecompound was subjected to variable gradient chromatography on silica gelwith dichloromethane/methanol mixtures and yielded1-methyl-2-pyrrolidinone. The mixture was dissolved in dichloromethaneand extracted with water (520 mL). The organic layer was dried overanhydrous. Sodium sulfate and evaporated to an off white solid. Theproduct was characterized by ¹H-NMR and purity checked by RP-HPLC (YMCC-18 column; 50×4.4 mm; S-5 120 A° 0.1% TFA-water/0.1%TFA-acetonitrile).

[0096] Table 2, below identifies compounds of this invention that wereprepared according to the general synthesis method set forth in thisExample. In Table 2, MS=Mass Spectrum and MH+=mass of parent molecularion plus one hydrogen atom. TABLE 2 COMPOUNDS PREPARED BY METHOD OFEXAMPLE 2 R₁X R₂ R₃ MS(MH+) (4-Methylphenyl)methylamino Isopropyl2-Aminoethylamino 340 (2,4-Dichlorophenyl)methylamino IsopropylDiethanolamino 439 (2,4-Dichlorophenyl)methylamino Isopropyl2-Aminoethylamino 394 (3-Methylphenyl)methylamino IsopropylDiethanolamino 385 (3-Methylphenyl)methylamino Isopropyl2-Aminoethylamino 340 (3-Methylphenyl)methylamino Isopropyl2-(N2-Dimethylamino)-N1- 458 benzylethylamino(4-Trifluoromethylphenyl)methylamino Isopropyl 2-Aminoethylamino 394(4-Trifluoromethylphenyl)methylamino Isopropyl 1-Hydroxymethyl-2- 437methylpropylamino (3,5-Bis- Isopropyl Diethanolamino 507trifluoromethylphenyl)methylamino (3,5-Bis- Isopropyl 2-Aminoethylamino462 trifluoromethylphenyl)methylamino (3,5-Bis- Isopropyl1-Hydroxymethyl-2- 505 trifluoromethylphenyl)methylaminomethylpropylamino (3-Chlorophenyl)methylamino Isopropyl1-Hydroxymethylethylamino 375 (2-Trifluoromethyl-phenyl)methylaminoIsopropyl 1-Hydroxymethylethylamino 409 (4-Chloro-3-trifluoromethyl-Isopropyl 1-Hydroxymethylethylamino 443 phenyl)methylamino(3-Chlorophenyl)methylamino Isopropyl 2-Hydroxyethylamino 361(2-Trifluromethyl-phenyl)methylamino Isopropyl 2-Hydroxyethylamino 395(4-Chloro-3-trifluoromethyl- Isopropyl 2-Hydroxyethylamino 429phenyl)methylamino (3-Chlorophenyl)methylamino Isopropyl(1R,2S)-2-Hydroxy-1- 451 methyl-2-phenethylamino(2-Chlorophenyl)methylamino Isopropyl Diethanolamino 450(2,5-Difluorophenyl)methylamino Isopropyl Diethanolamino 407(1-Naphthyl)methylamino Isopropyl Diethanolamino 421(2-Chlorophenyl)methylamino Isopropyl 2-Aminoethylamino 360(2,5-Difluorophenyl)methylamino Isopropyl 2-Aminoethylamino 362(1-Naphthyl)methylamino Isopropyl 2-Aminoethylamino 376(2-Chlorophenyl)methylamino Isopropyl 1-Hydroxymethyl-2- 403methylethylamino (2,5-Difluorophenyl)methylamino Isopropyl1-Hydroxymethyl-2- 405 methylethylamino (1-Naphthyl)methylaminoIsopropyl 1-Hydroxymethyl-2- 419 methylethylamino(3-Methylphenyl)methylamino Isopropyl 2-Aminopropylamino 354(2-Chlorophenyl)methylamino Isopropyl 2-Aminopropylamino 374(3-Chlorophenylmethylamino Isopropyl 2-Aminopropylamino 374(2,5-Difluorophenyl)methylamino Isopropyl 2-Aminopropylamino 376(1-Naphthyl)methylamino Isopropyl 2-Aminopropylamino 390 (2-Chloro-5-Isopropyl Diethanolamino 473 trifluoromethylphenyl)methylamimo(3-Chlorophenyl)methylamino Isopropyl 1-Hydroxymethyl-2- 403methylpropylamino (2-Trifluoromethylphenyl)methylamino Isopropyl1-Hydroxymethyl-2- 437 methylpropylamino (3-Methylphenyl)methylaminoIsopropyl 2-(2-Hydroxyethylamino)- 384 ethylamino(2-Chlorophenyl)methylamino Isopropyl 2-(2-Hydroxyethylamino)- 404ethylamino (3-Chlorophenyl)methylamino Isopropyl2-(2-Hydroxyethylamino)- 404 ethylamino (2,5-Difluorophenyl)methylamimoIsopropyl 2-(2-Hydroxyethylamino)- 406 ethylamino(1-Naphthyl)methylamino Isopropyl 2-(2-Hydroxyethylamino)- 420ethylamino (3,5-Bistrifluoromethyl- Isopropyl 2-(2-Hydroxyethylamino)-506 phenyl)methylamino ethylamino (4-Isopropylphenyl)methylaminoIsopropyl 2-(2-Hydroxyethylamino)- 412 ethylamino(2-Trifluoromethylphenyl)methylamino Isopropyl 2-(2-Hydroxyethylamino)-438 ethylamino (4-Methylphenyl)methylamino Isopropyl2-(2-Hydroxyethylamino)- 384 ethylamino (4-Chloro-3- Isopropyl2-(2-Hydroxyethylamino)- 472 trifluoromethylphenyl)methylaminoethylamino (2-Chloro-5- Isopropyl 2-(2-Hydroxyethylamino)- 472trifluoromethylphenyl)methylamino ethylamino(3,5-Dichlorophenyl)methylamino Isopropyl 2-(2-Hydroxyethylamino)- 438ethylamino (1R)-(4-Methylphenyl)ethylamino Isopropyl2-(2-Hydroxyethylamino)- 398 ethylamino (1R)-(2-Naphthyl)ethylaminoIsopropyl 2-(2-Hydroxyethylamino)- 434 ethylamino (2,4-Dichloro-6-Isopropyl 2-(2-Hydroxyethylamino)- 452 methylphenyl)methylaminoethylamino (4-Trifluoromethylphenyl)methylamino Isopropyl2-(2-Hydroxyethylamino)- 438 ethylamino (3-Methylphenyl)methylaminoIsopropyl (2S)-pyrrolomethylamino 380 (2-Chlorophenyl)methylaminoIsopropyl (2S)-pyrrolomethylamino 400 (3-Chlorophenyl)methylaminoIsopropyl (2S)-pyrrolomethylamino 400 (2,5-Difluorophenyl)methylaminoIsopropyl (2S)-pyrrolomethylamino 402 (1-Naphthyl)methylamino Isopropyl(2S)-pyrrolomethylamino 416 (3,5-Bistrifluoromethyl- Isopropyl(2S)-pyrrolomethylamino 502 phenyl)methylamino(4-Isopropylphenyl)methylamino Isopropyl (2S)-pyrrolomethylamino 408(2-Trifluoromethylphenyl)methylamino Isopropyl (2S)-pyrrolomethylamino434 (4-Methylphenyl)methylamino Isopropyl (2S)-pyrrolomethylamino 380(4-Chloro-3- Isopropyl (2S)-pyrrolomethylamino 468trifluoromethylphenyl)methylamino (2-Chloro-5- Isopropyl(2S)-pyrrolomethylamino 468 trifluoromethylphenyl)methylamino(3,5-Dichlorophenyl)methylamino Isopropyl (2S)-pyrrolomethylamino 434(1R)-(4-Methylphenyl)ethylamino Isopropyl (2S)-pyrrolomethylamino 394(1R)-(2-Naphthyl)ethylamino Isopropyl (2S)-pyrrolomethylamino 430(2,4-Dichloro-6- Isopropyl (2S)-pyrrolomethylamino 448methylphenyl)methylamino (4-Trifluoromethylphenyl)methylamino Isopropyl(2S)-pyrrolomethylamino 434 (3-Methylphenyl)methylamino Isopropyl2-Hydroxy-1-(S)- 355 methylethylamino (2-Chlorophenyl)methylaminoIsopropyl 2-Hydroxy-1-(S)- 375 methylethylamino(2,5-Difluorophenyl)methylamino Isopropyl 2-Hydroxy-1-(S)- 377methylethylamino (1-Naphthyl)methylamino Isopropyl 2-Hydroxy-1-(S)- 391methylethylamino (3,5-Bistrifluoromethyl- Isopropyl 2-Hydroxy-1-(S)- 477phenyl)methylamino methylethylamino (4-Isopropylphenyl)methylaminoIsopropyl 2-Hydroxy-1-(S)- 383 methylethylamino(4-Methylphenyl)methylamino Isopropyl 2-Hydroxy-1-(S)- 355methylethylamino (2-Chloro-5- Isopropyl 2-Hydroxy-1-(S)- 443trifluoromethylphenyl)methylamino methylethylamino (5-Fluoro-2-Isopropyl 2-Hydroxy-1-(S)- 427 trifluoromethylphenyl)methylaminomethylethylamino (3,5-Dichlorophenyl)methylamino Isopropyl2-Hydroxy-1-(S)- 409 methylethylamino [R]-1-(4-Methylphenyl)ethylaminoIsopropyl 2-Hydroxy-1-(S)- 369 methylethylamino[R]-1-(2-Naphthyl)ethylamino Isopropyl 2-Hydroxy-1-(S)- 405methylethylamino (2,4-Dichlorophenyl)methylamino Isopropyl2-Hydroxy-1-(S)- 409 methylethylamino (2,4-Dichloro-6- Isopropyl2-Hydroxy-1-(S)- 423 methylphenyl)methylamimo methylethylamino(4-Trifluoromethylphenyl)methylamino Isopropyl 2-Hydroxy-1-(S)- 409methylethylamino (3-Methylphenyl)methylamino Isopropyl2-Hydroxyethlamino 341 (2-Chlorophenyl)methylamino Isopropyl2-Hydroxyethylamino 361 (2,5-Difluorophenyl)methylamino Isopropyl2-Hydroxyethylamino 363 (1-Naphthyl)methylamino Isopropyl2-Hydroxyethylamino 377 (3,5-Bistrifluoromethyl- Isopropyl2-Hydroxyethylamino 463 phenyl)methylamino(4-Isopropylphenyl)methylamino Isopropyl 2-Hydroxyethylamino 369(4-Methylphenyl)methylamino Isopropyl 2-Hydroxyethylamino 341(2-Chloro-5- Isopropyl 2-Hydroxyethylamino 429trifluoromethylphenyl)methylamino (5-Fluoro-2- Isopropyl2-Hydroxyethylamino 413 trifluoromethylphenyl)methylamino(3,5-Dichlorophenyl)methylamino Isopropyl 2-Hydroxyethylamino 395(1R)-(4-Methylphenyl)ethylamino Isopropyl 2-Hydroxyethylamino 355(1R)-(2-Naphthyl)ethylamino Isopropyl 2-Hydroxyethylamino 391(2,4-Dichlorophenyl)methylamino Isopropyl 2-Hydroxyethylamino 395(2,4-Dichloro-6- Isopropyl 2-Hydroxyethylamino 409methylphenyl)methylamino (4-Trifluoromethylphenyl)methylamino Isopropyl2-Hydroxyethylamino 395 (3-Methylphenyl)methylamino Isopropyl 1- 369Hydroxymethylpropylamino (2-Chlorophenyl)methylamino Isopropyl 1- 389Hydroxymethylpropylamino (3-Chlorophenyl)methylamino Isopropyl 1- 389Hydroxymethylpropylamino (2,5-Difluorophenyl)methylamino Isopropyl 1-391 Hydroxymethylpropylamino (1-Naphthyl)methylamino Isopropyl 1- 405Hydroxymethylpropylamino (3,5-Bistrifluoromethyl- Isopropyl 1- 491phenyl)methylamino Hydroxymethylpropylamino(4-Isopropylphenyl)methylamino Isopropyl 1- 397 Hydroxymethylpropylamino(2-Trifluoromethylphenyl)methylamino Isopropyl 1- 423Hydroxymethylpropylamino (4-Methylphenyl)methylamino Isopropyl 1- 369Hydroxymethylpropylamino (4-Chloro-3- Isopropyl 1- 457trifluoromethylphenyl)methylamino Hydroxymethylpropylamino (2-Chloro-5-Isopropyl 1- 457 trifluoromethylphenyl)methylaminoHydroxymethylpropylamino (5-Fluoro-2- 1- 441trifluoromethylphenyl)methylamino Hydroxymethylpropylamino(3,5-Dichlorophenyl)methylamino Isopropyl 1- 423Hydroxymethylpropylamino (1R)-(4-Methylphenyl)ethylamino Isopropyl 1-383 Hydroxymethylpropylamino (1R)-(2-Naphthyl)ethylamino Isopropyl 1-419 Hydroxymethylpropylamino (2,4-Dichlorophenyl)methylamino Isopropyl1- 423 Hydroxymethylpropylamino (2,4-Dichloro-6- Isopropyl 1- 437methylphenyl)methylamino Hydroxymethylpropylamino(4-Trifluoromethylphenyl)methylamino Isopropyl 1- 423Hydroxymethylpropylamino (3,5-Dichlorophenyl)methylamino Isopropyl2-(2-Hydroxyethylamino)- 438 ethylamino (3,5-Dichlorophenyl)methylaminoIsopropyl (2S)-pyrrolomethylamino 434 (4-Chlorophenyl)methylaminoIsopropyl 2-Aminocyclohexylamino 414 (4-Chlorophenyl)methylaminoIsopropyl 3-Aminocyclohexylamino 414 (3-Fluoro-6-trifluoromethyl-Isopropyl Diethanolamino 457 phenyl)methylamino(2-Chloro-5-trifluoromethyl- Isopropyl 2-Aminoethylamino 428phenyl)methylamino (3,5-Bis-trifluoromethyl- Isopropyl2-Aminopropylamino 476 phenyl)methylamino(2-Trifluoromethyl-phenyl)methylamino Isopropyl 2-Aminopropylamino 408(4-methylphenyl)methylamino Isopropyl 2-Aminopropylamino 354(4-Chloro-3-trifluoromethyl- Isopropyl 2-Aminopropylamino 442phenyl)methylamino (2-Chloro-5-trifluoromethyl- Isopropyl2-Aminopropylamino 442 phenyl)methylamino[R]-1-(4-methylphenyl)ethylamino Isopropyl 2-aminoethylamino 354[R]-1-(2-Naphthyl)ethylamino Isopropyl 2-Aminoethylamino 390(2-Chloro-5-trifluoromethyl- Isopropyl 1-Hydroxymethyl-2- 471phenyl)methylamino methylpropylamino (3-fluoro-6-trifluoromethyl-Isopropyl 1-Hydroxymethyl-2- 455 phenyl)methylamino methylpropylamino[R]-1-(4-methylphenyl)ethylamino Isopropyl 2-Aminopropylamino 368[R]-1-2-Naphthyl)ethylamino Isopropyl 2-Aminopropylamino 404(4-Trifluoromethyl-phenyl)methylamino Isopropyl 2-Aminopropylamino 408(3-Methylphenyl)methylamino Isopropyl 2-Amino-2- 368 methylpropylamino(2-Chlorophenyl)methylamino Isopropyl 2-Amino-2- 388 methylpropylamino(3-Chlorophenyl)methylamino Isopropyl 2-Amino-2- 388 methylpropylamino(2,5-Difluorophenyl)methylamino Isopropyl 2-Amino-2- 390methylpropylamino (1-Naphthyl)methylamino Isopropyl 2-Amino-2- 404methylpropylamino (3,5-Bis-trifluoromethyl- Isopropyl 2-Amino-2- 490phenyl)methylamino methylpropylamino(2-Trifluoromethyl-phenyl)methylamino Isopropyl 2-Amino-2- 422methylpropylamino (4-Methylphenyl)methylamino Isopropyl 2-Amino-2- 368methylpropylamino (4-Chloro-3-trifluoromethyl- Isopropyl 2-Amino-2- 456phenyl)methylamino methylpropylamino (2-Chloro-5-trifluoromethyl-Isopropyl 2-Amino-2- 456 phenyl)methylamino methylpropylamino(3-Fluoro-6-trifluoromethyl- Isopropyl 2-Amino-2- 440 phenyl)methylaminomethylpropylamino [R]-1-(4-Methylphenyl)methylamino Isopropyl 2-Amino-2-382 methylpropylamino [R]-1-(2-Naphthyl)ethylamino Isopropyl 2-Amino-2-418 methylpropylamino (4-Trifluoromethyl-phenyl)methylamino Isopropyl2-Amino-2- 422 methylpropylamino

EXAMPLE 3

[0097] This Example describes a method for preparing compounds of thisinvention. The synthesis method disclosed in this Example is onlyslightly modified from that disclosed in Example 1.

[0098] The following compound was prepared according to the methodabove.

Preparation of 2,6-dichloro-9-isopropylpurine (4).

[0099] To a solution of 0.67 g of 2,6-dichloropurine in 5 mL of dry DMFat room temperature was added 0.16 gms (1.1 eq.) of 50% sodiumhydride/oil powder. Upon cessation of Adhydrogen evolution, a largeexcess (2 mL) of isopropyl iodide was added to the anionic solution.This reaction solution was stirred for three days at ambienttemperature. The reaction was quenched with 30 mL of water and extractedwith ethyl acetate (350 mL). The organic extracts were combined and backwashed with 350 mL of water followed by 20 mL of brine. The ethylacetate solution was dried over anhydrous magnesium sulfate andevaporated. The compound was subjected to variable gradient flashchromatography on silica gel with hexane/ethyl acetate mixtures andyielded the N-9 product and the N-7 isomer.

Preparation of 2-chloro-6-anilino-9-isopropylpurine (5).

[0100] 2,6-dichloro-9-isopropylpurine (0.019 g, 0.081 mmol) wasdissolved in butanol (0.5 ml) and aniline (0.044 ml, 0.244 mmol) wasadded. The reaction mixture was heated to 120° C. for 10 hr, cooled,diluted with EtOAc and washed 3 times with water. The mixture was driedover MgSO₄ and concentrated to an off white solid.

Preparation of 2-diethanolamino-6-(4-phenylanilino)-9-isopropylpurine(6).

[0101] A solution of 67 mgs of 2,6-dichloro-N-9-isopropylpurine and 100mgs of 4-phenylaniline in 1 mL of n-octanol was heated to 80° C. for 24hours. The n-octanol was removed in vacuo and then replaced with 1 mL of40% diethanolamine in DMSO. The solution was heated at 130° C. for 48hours. The reaction was cooled to ambient temperature then diluted with10 mL of water and subsequently extracted with ethyl acetate (3×30 mL).The organic extracts were combined and back washed with 3×20 mL of waterfollowed by 10 mL of brine. The ethyl acetate solution was dried overanhydrous magnesium sulfate and filtered and the solvent was evaporated.The 65 mgs of crude product was crystallized from THF-ether solution.

[0102] Table 3 below identifies compounds of this invention that wereprepared according to the general synthesis method set forth in thisExample. TABLE 3 Compounds Prepared By The Method Of Example 3 R₁X R₂ R₃(8-quinolinyl)amino Isopropyl CI (6-quinolinyl)amino Isopropyl CI(3-quinolinyl)amino Isopropyl CI anilino Isopropyl CI 3,5-dinitroanilinoIsopropyl CI 4-butylanilino Isopropyl CI (8-quinolinyl)amino IsopropylDiethanolamino (6-quinolinyl)amino Isopropyl Diethanolamino(3-quinolinyl)amino Isopropyl Diethanolamino anilino IsopropylDiethanolamino 3,5-dinitroanilino Isopropyl Diethanolamino4-butylanilino Isopropyl Diethanolamino (6-ethoxy-2-benzothiazolyl)aminoIsopropyl CI 4-morpholino-2-methylamino Isopropyl CI(4-aminosulfonyl-phenyl)methylamino Isopropyl CI 4-bromoanilinoIsopropyl diethanolamino 3,4-dichloroanilino Isopropyl diethanolamino2-(2-(1-methyl)pyrrolidinyl)ethylamino Isopropyl diethanolamino3-bromoanilino Isopropyl CI 4-methoxyanilino Isopropyl diethanolamino4-iodoanilino Isopropyl CI 3-iodoanilino Isopropyl CI 3-methoxyanilinoIsopropyl CI 2-(1-piperidinyl)ethylamino Isopropyl diethanolamino2-(1-pyrrolidinyl)ethylamino Isopropyl diethanolamino (1-indanyl)aminoIsopropyl diethanolamino 2-(6-ethoxybenzothiazolyl)amino Isopropyldiethanolamino 4-morpholino-2-methylamimo Isopropyl diethanolamino(4-aminosulfonyl-phenyl)methylamino Isopropyl diethanolamino4-bromoanilino Isopropyl diethanolamino 3,4-dichloroanilino Isopropyldiethanolamino 2-(2-(1-methyl)pyrrolidinyl)ethylamino Isopropyldiethanolamino 3-bromoanilino Isopropyl diethanolamino 4-methyoxyanilinoIsopropyl diethanolamino 4-iodoanilino Isopropyl diethanolamino3-iodoanilino Isopropyl diethanolamino 3-methoxylanilino Isopropyldiethanolamino 2-(1-piperidinyl)ethylamino Isopropyl diethanolamino2-(1-pyrrolidinyl)ethylamino Isopropyl diethanolamino (1-indanyl)aminoIsopropyl diethanolamino 3-iodonilino Isopropyl diethanolamino3-phenoxyanilino Isopropyl diethanolamino 4-iodoanilino Isopropyldiethanolamino 4-phenoxyanilino Isopropyl diethanolamino3-phenoxyanilino Isopropyl diethanolamino 2-fluorenylamino Isopropyldiethanolamino 1-fluorenylamino Isopropyl diethanolamino2-anthracenylamino Isopropyl diethanolamino 1-anthracenylamino Isopropyldiethanolamino 2-(6-ethoxybenzothiazol)amino Isopropyl diethanolamino(1-indanyl)amino Isopropyl diethanolamino 2-(6-ethoxybenzothiazol)aminoIsopropyl diethanolamino 4-morpholino-2-methylamino Isopropyldiethanolamino (4-aminosulfonyl-phenyl)methylamino Isopropyldiethanolamino 4-bromoanilino Isopropyl diethanolamino3,4-dichloroanilino Isopropyl diethanolamino2-(2-(1-methyl)pyrrolidinyl)ethylamino Isopropyl diethanolamino3-bromoanilino Isopropyl diethanolamino 4-methoxyanilino Isopropyldiethanolamino 4-iodoanilino Isopropyl diethanolamino 3-iodoanilinoIsopropyl diethanolamino 3-methoxyanilino Isopropyl diethanolamino2-(1-piperidinyl)ethylamino Isopropyl diethanolamino2-(1-pyrrolidinyl)ethylamino Isopropyl diethanolamino (1-indanyl)aminoIsopropyl diethanolamino 3-iodoanilino Isopropyl diethanolamino3-pheoxyanilino Isopropyl diethanolamino 4-iodonilino Isopropyldiethanolamino 4-phenoxyanilino Isopropyl diethanolamino3-phenoxyanilino Isopropyl diethanolamino 2-fluorenylamino Isopropyldiethanolamino 1-fluorenylamino Isopropyl diethanolamino2-anthracenylamino Isopropyl diethanolamino 1-anthracenylamino Isopropyldiethanolamino 2-(6-ethoxybenzothiazolyl)amino Isopropyl diethanolamino(2-biphenyl)methylamino Isopropyl diethanolamino (4-biphenyl)methylaminoIsopropyl diethanolamino 2-naphthylmethylamino Isopropyl diethanolamino1-naphthylmethylamino Isopropyl diethanolamino(4-Chlorophenyl)methylamino Isopropyl Diethanolamino(4-Fluorophenyl)methylamino Isopropyl Diethanolamino(4-Methoxyphenyl)methylamino Isopropyl 5-Aminopentylamino(4-Trifluoromethylphenyl)methylamino Isobutyl Diethanolamino(4-Trifluoromethylphenyl)methylamino Isopropyl Diethanolamino(4-Chlorophenyl)methylamino Isopropyl (S)-2-Amino-3- phenylpropylamino(4-Fluorophenyl)methylamino Isopropyl 2-Aminoethylamino(4-Fluorophenyl)methylamino Isopropyl (D)-1-Hydroxymethyl-2-methyl-propylamino (4-Fluorophenyl)methylamino Isopropyl(L)-1-Hydroxymethyl-2- methyl-propylamino (4-Chlorophenyl)methylaminoIsopropyl (D)-1-Hydroxymethyl-2- methyl-propylamino(4-Chlorophenyl)methylamino Isopropyl (L)-1-Hydroxymethyl-2-methyl-propylamino (4-Chlorophenyl)methylamino Isopropyl2-Hydroxy-2-phenyl- ethylamino (4-Chlorophenyl)methylamino Isopropyl2-Amino-N1-(2- hydroxyethyl)ethylamino (4-Chlorophenyl)methylaminoIsopropyl 2-Amino-N2-(2- hydroxyethyl)ethylamino(4-Chlorophenyl)methylamino Isopropyl (S)-2-Phenyl-1-carboxamido-ethylamino (4-Chlorophenyl)methylamino Isopropyl 2-Amino-N2-(2-hydroxyethyl)-N1- (hydroxyethyl)ethylamino(4-Sulfonamidophenyl)methylamino Isopropyl 2-Aminoethylamino(4-Fluorophenyl)methylamino 2-Oxo-3-butyl Diethanolamino(4-Fluorophenyl)methylamino 2-Oxo-3-butyl 2-Aminoethylamino(4-Chlorophenyl)methylamino 2-Oxo-3-butyl Diethanolamino(4-Chlorophenyl)methylamino 2-Oxo-3-butyl 2-Aminoethylamino(4-Methylphenyl)methylamino Isopropyl 1-Hydroxymethyl-2-methyl-propylamino (3-Methylphenyl)methylamino Isopropyl1-Hydroxymethyl-2-methyl- propylamino (4-Chlorophenyl)methylaminoIsopropyl 2-(N2-dimethylamino)-N1- benzyl-ethylamino(4-Chlorophenyl)methylamino Isopropyl 1-Carboxamido-2-methyl-propylamino (4-Chlorophenyl)methylamino Isopropyl 2-Aminoethylamino(4-Chlorophenyl)methylamino Isopropyl 3-Aminopropylamino(4-Chlorophenyl)methylamino Isopropyl 5-Aminopentylamino(4-Chlorophenyl)methylamino Isopropyl 2-Amino-2-methyl- ethylamino(4-Chlorophenyl)methylamino Isopropyl (S)-(+)-1-(Hydroxymethyl)propylamino (4-Chlorophenyl)methylamino Isopropyl(R)-(−)-1- (Hydroxymethyl)propylamino (4-Chlorophenyl)methylamimoIsopropyl (S)-(+)-1- (Hydroxymethyl)ethylamino(4-Chlorophenyl)methylamino Isopropyl (R)-(−)-1-(Hydroxmethyl)ethylamino (4-Chlorophenyl)methylamino Isopropyl(S)-(+)-2- Hydroxypropylamino (4-Chlorophenyl)methylamino Isopropyl(R)-(−)-2- Hydroxypropylamino (4-Fluorophenyl)methylamino Isopropyl2-Amino-propylamino (3-Chlorophenyl)methylamino Isopropyl Diethanolamino(3-Chlorophenyl)methylamino Isopropyl 2-Aminoethylamino(2-Trifluoromethylphenyl)methylamino Isopropyl Diethanolamino(2-Trifluoromethylphenyl)methylamino Isopropyl 2-Aminoethylamino(4-Chloro-3-trifluoromethylphenyl) Isopropyl Diethanolamino methylamino(4-Chloro-3-trifluoromethylphenyl) Isopropyl 2-Aminoethylaminomethylamino (3,5-Dichlorophenyl)methylamino Isopropyl Diethanolamino(3,5-Dichlorophenyl)methylamino Isopropyl 2-Amino-ethylamino(2-Trifluoromethyl-phenyl)methylamino Isopropyl 2-(N2-dimethylamino)-N1-benzyl-ethylamino (3-Chlorophenyl)methylamino Isopropyl Diethanolamino(3-Chlorophenyl)methylamino Isopropyl 2-Aminoethylamino(2-Trifluoromethylphenyl)methylamino Isopropyl Diethanolamino(2-Trifluoromethylphenyl)methylamino Isopropyl 2-Aminoethylamino(4-Chloro-3- Isopropyl Diethanolamino trifluoromethylphenyl)methylamino(4-Chloro-3- Isopropyl 2-Aminoethylaminotrifluoromethylphenyl)methylamino (3,5-Dichlorophenyl)methylaminoIsopropyl Diethanolamino (3,5-Dichlorophenyl)methylamino Isopropyl2-Aminoethylamino (2-Trifluoromethylphenyl)methylamino Isopropyl2-(N2-Dimethylamino)-N1- benzylethylamino (3-Chlorophenyl)methylaminoIsopropyl 2-(N2-Dimethylamino)-N1- benzylethylamino(3,5-Dichlorophenyl)methylamino Isopropyl 2-(N2-Dimethylamino)-N1-benzylethylamino (4-Chloro-3- Isopropyl 2-(N2-Dimethylamino)-N1-trifluoromethylphenyl)methylamino benzylethylamino(4-Chlorophenyl)methylamino Isopropyl 2-Amino-2- methylpropylamino(4-Fluorophenyl)methylamino Isopropyl (S)-(2-Tetrahydrofuranyl)methylamimo (4-Fluorophenyl)methylamino Isopropyl(R)-(2- Tetrahydrofuranyl)methylamimo (4-Methylphenyl)methylaminoIsopropyl Diethanolamino (4-Fluorophenyl)methylamino Isopropyl2-Hydroxy-1- methylethylamino (4-Fluorophenyl)methylamino Isopropyl(S)-2-Hydroxy-2- methylethylamino (4-Fluorophenyl)methylamino Isopropyl(R)-2-Hydroxy-2- methylethylamino (4-Fluorophenyl)methylamino Isopropyl1- Hydroxymethylpropylamino (4-Fluorophenyl)methylamino Isopropyl2-Amino-2- methylpropylamino

EXAMPLE 4

[0103] This Example describes a method for preparing compounds of thisinvention. The synthesis method disclosed in this Example is onlyslightly modified from that disclosed in Example 1.

[0104] The following compound was prepared according to the methodabove.

Preparation of 2,6-dichloro-9-isopropylpurine (4).

[0105] The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55ml of dry DMF at room temperature and treated with sodium hydride, 60%dispersion (1.27 g, 31.75 mmol) added in portions. After stirring for 1hr, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reactionstirred for 2 days. The reaction was poured into diethyl ether andwashed once with saturated sodium bicarbonate solution and once withwater. The mixture was dried over anhydrous sodium sulfate andconcentrated in vacuo. The concentrate was chromatographed over silicagel eluting with 10% acetone in dichloromethane solution to give thedesired N-9 alkylation product as a white solid.

Preparation of 2-chloro-6-(4-methylmercapto) anilino-9-isoproplypurine(5A).

[0106] 2,6-Dichloro-9-isopropylpurine (0.15 g, 0.649 mmol) was dissolvedin n-butanol (4 ml) and 4-(methylmercapato) aniline (0.089 ml, 0.714mmol) and triethylamine (0.20 ml, 1.43 mmol) were added. The reactionmixture was heated at 80° overnight. The cooled reaction was dilutedethyl acetate and washed 1×1M HCI, 1× saturated sodium bicarbonate, and1× brine before being dried with anhydrous sodium sulfate andconcentrated in vacuo. The residue was chromatographed over silica geland eluting with 2% methanol in dichloromethane to give the desiredproduct as a white solid.

Preparation of 2-diethanolamine-6-(4-methylmercapto)anilino-9-isopropylpurine (6A).

[0107] The purine (0.18 g, 539 mmol) was dissolved inN-methylyrrolidinone (3 ml) and diethanolamine (1 ml) and then heated at120° C. overnight. The cooled reaction was poured into diethyl ether andwashed three times with water before drying over anhydrous sodiumsulfate and concentrating in vacuo. The residue was chromatographed oversilica gel eluting with 5% methanol in dichloromethane to give thedesired product as an off-white solid. ¹H-NMR(δ, CDCl₃): 8.08(s,1H),7.58(d, 2H), 7.47(s, 1H), 7.18(d, 2H), 4.95(br s, <2H), 4.52(m, 1H),3.94(m, 4H), 3.83(m,4H), 2.43(s, 3H), 1.47(d, 6H).

Preparation of 4-(2-thienyl) benzonitrile.

[0108] Some R₁′ groups must first be synthesized before reacting withthe 2,6-dichloro-9-isopropylpurine. These groups can be synthesizedthrough various coupling methods and other synthetic procedures known tothose skilled in the art of organic synthesis.

[0109] To a pressure tube was added 4-bromobenzonitrile (0.20 g, 1.10mmol), tetrakis(triphenylphosphine) palladium (0) (0.127 g, 0.1 eq) and2-thiopheneboronic acid (0.211 g, 1.65 mmol). The reaction was flushedunder vacuum and flushed with dry nitrogen three times. Followingflushes, ethyleneglycol dimethyl ether (5.5 ml) and an aqueous solutionof sodium carbonate (2.53 ml, 1M) were added to the tube. The tube wasthen sealed and heated at 80° C. overnight. The cooled reaction was thediluted with diethyl ether and washed twice with water before dryingover sodium sulfate and concentrating in vacuo. The residue waschromatographed over silica gel eluting with 10% ethyl acetate in hexaneto give the desired product as a white solid.

Preparation of 4-(2-thienyl) benzylamine.

[0110] The 4-(2-thienyl)benzonitrile (0.086 g, 0.464 mmol) was dissolvedin dry tetrahydrofuran (1.6 ml) before lithium aluminum hydride (0.46ml, 0.464 mmol, 1 M in THF) was added dropwise. The reaction was allowedto stir at room temperature overnight. TLC (5% methanol indichloromethane) still showed starting material remaining. Another 1 eqof LAH was added. After an additional hour, the reaction was quenched bythe Fieser and Fieser method using wager (17.46 μl), aqueous sodiumhydroxide solution (17.46 μl, 15% soln.), and water (52.37 μl) addedsequentially to the reaction. The reaction was then diluted with diethylether and water and extracted twice with diethyl ether before dryingover sodium sulfate and concentrating in vacuo. The residue was carriedon crude without any further purification.

[0111] Table 3 below identified compounds of this invention that wereprepared according to the general synthesis method set forth in thisExample. TABLE 4 Compounds Prepared By The Method of Example 4 R₁′-X R2R3 Cl Me Cl ethanolamino Me ethanolamino cyclopropylmethylaminoisopropyl Cl cyclopropylmethylamino isopropyl diethanolamino3,5-dinitroanilino isopropyl Cl 3-phenoxyanilino isopropyl Cl4-iodoanilino isopropyl Cl 3-aminoquinolino isopropyl Cl3,5-dinitroanilino isopropyl diethanolamino Cl epoxymethyl Cl4-methoxybenzylamino 2,3-dihydroxypropyl diethanolamino 4-phenylanilinoisopropyl diethanolamino 4-phenylbenzylamino isopropyl Cl2-naphthalenylmethylamino isopropyl Cl 1-naphthalenylmethylaminoisopropyl Cl 2-phenylbenzylamino isopropyl Cl 3-quinolinylaminoisopropyl diethanolamino 5-quinolinylamino isopropyl diethanolamino6-quinolinylamino isopropyl diethanolamino 8-quinolinylamino isopropyldiethanolamino n-butylamino isopropyl Cl 4-(2-thiophenyl)benzylaminoisopropyl diethanolamino 4-(2-thiophenyl)benzylamino isopropyl Cl3-thiomethoxyanilino isopropyl Cl 4-thiomethoxyanilino isopropyl Cl3-thiomethoxyanilino isopropyl diethanolamino 4-thiomethoxyanilinoisopropyl diethanolamino 4-(2-pyridinyl) benzylamino isopropyl Cl3-methoxybenzylamino isopropyl Cl 3,4-dimethoxybenzylamino isopropyl Cl3,4,5-trimethoxyenzylamino isopropyl Cl 3-methoxybenzylamino isopropyldiethanolamino 3,4-dimethoxybenzylamino Isopropyl diethanolamino3,4,5-trimethoxyenzylamino Isopropyl diethanolamino4-(3-thiophenyl)benzylamino Isopropyl Cl 4-(4-methoxphenyl) benzylaminoIsopropyl Cl 4-(4-bromophenyl) benzylamino Isopropyl diethanolamino4-(3-methoxyphenyl) benzylamino Isopropyl diethanolamino4-(4-methoxyphenyl) benzylamino Isopropyl diethanolamino4-(3-thiophenyl) benzylamino Isopropyl diethanolamino 4-(3-methylphenyl)benzylamino Isopropyl Cl 4-(4-methylphenyl) benzylamino Isopropyl Cl4-(4-trifluoromethylphenyl) Isopropyl Cl benzylamino 3-(4nitrilophenyl)anilino Isopropyl Cl 3-(4-nitrilophenyl)anilino Isopropyldiethanolamino 4-(2-pyridinyl)benzylamino Isopropyl Cl4-(2-pyridinyl)benzylamino Isopropyl diethanolamino

EXAMPLE 5

[0112] This Example describes a method for preparing compounds of thisinvention. The synthesis method disclosed in this Example is onlyslightly modified from that disclosed in Example 1.

[0113] The following compound was prepared according to the methodabove.

Preparation of 2-amino-6-chloro-9-methylpurine (7).

[0114] The 2-amino-6-chloropurine (1.08 g, 6.4 mmol) was suspended indry DMF (75 ml) and treated with sodium hydride, 60% dispersion (0.28 g,7 mmol). The suspension was stirred for 15 min before iodomethane (0.44ml, 7.06 mmol) was added and the resulting yellow solution stirred for 1hr 45 min. The solid was filtered and the filtrate evaporated beforeaddition of water for 10 min. The resulting solid was filtered and driedovernight to give the product as a mixture of N-7 and N-9 alkylationproducts. The residual liquor was left overnight and more crystals werecollected the next day and dried.

Preparation of 6-chloro-2-(2-methoxyacetylamino)-9-methylpurine (8).

[0115] The mixture of isomers from above was dissolved indichloromethane and pyridine (2 eq) followed by treatment withmethoxyacetyl chloride (4 eq). The reaction was stirred at roomtemperature until complete. The reaction was evaporated and filteredthrough a plug of silicia gel eluting with 2% methanol indichloromethane followed by purification on a chomatotron using silicagel and eluting with 2% methanol in dichloromethane to isolate thedesired product.

[0116] Table 5 identifies compounds of this invention that were preparedaccording to the synthesis method set forth in this Example. TABLE 5Compounds Prepared By The Method of Example 5 R1 R2 R3 Cl Me H Cl Me2-methoxyethylamino

EXAMPLE 6

[0117] This Example describes a method for preparing compounds of thisinvention. The synthesis method disclosed in this Example is onlyslightly modified from that disclosed in Example 1.

[0118] The following compound was prepared according to the methodabove.

Preparation of 2-chloro-6-(4-phenyl benzylamino) purine (9).

[0119] The 2,6-dichloropurine (5.0 g, 26.45 mmol) was suspended inn-butanol (50 ml) and the 4-phenylbenzylamine (6.61 g, 29.1 mmol) andtriethylamine (4.1 ml, 29.1 mmol) were added. The solution was heated at120° C. overnight then cooled. Filtered off product using excessn-butanol and washed precipitate with 100 ml 1M HCl and 200 ml water.The solid was dried in vacuum over overnight at 70° C to give thedesired product as a pale yellow solid

Preparation of 2-diethanolamino-6-(4-phenyl benzylamino) purine (10).

[0120] The 2-chloro-6-(4-phenyl benzylamino) purine (2.0 g, 5.96 mmol)was added together with diethanolamine (11.4 ml, 119.2 mmol) andN-methylpyrrolidinone (10 ml) and heated at 120° C. overnight. Thecooled reaction was poured into dichloromethane and washed twice withwater. The organic layer was dried with anhydrous sodium sulfate andconcentrated in vacuo to give the desired product as a pale green solidwhich was further dried in vacuum oven at 70° C. for 2 days.

Preparation of 2-diethanolamino-6-(4-phenyl benzylamino)-9-methylpurine(11).

[0121] The 2-diethanolamino-6-(4-phenyl benzylamino) purine (0.050 g,0.124 mmol) was dissolved in dry DMF and treated wit sodium hydride, 60%dispersion (5.5 mgs, 0.136 mmol) for 1 hr. iodomethane (0.009 ml, 0.148mmol) was added and the resultant solution stirred at room temperatureovernight. Poured reaction into diethyl ether and washed twice withsaturated sodium bicarbonate solution before drying over anhydroussodium sulfate and concentrating in vacuo. The residue waschromatographed over silica gel eluting with 5% methanol indichloromethane to give the produce as a white solid. ₁H-NMR(δ, CDCl3):7.55 (m,4H), 7.41 (m, 4H) 7.35(m, 4H), 6.41 (br s, <1H), 5.10(br s,<2H), 4.72 (br s, 2H), 3.86 (m, 4H), 3.74(m, 4H), 3.59(s, 3H).

[0122] Table 5 identified compounds of this invention that were preparedaccording to the synthesis method set forth in this Example. TABLE 6Compounds Prepared By The Method of Example 6 R₁′-X R2 R34-phenylbenzylamino Methyl diethanolamino 4-phenylbenzylaminoCyclopentyl diethanolamino 4-phenylbenzylamino Allyl diethanolamino4-phenylbenzylamino Benzyl diethanolamino 4-phenylbenzylamino3-methylbutyl diethanolamino 4-phenylbenzylamino Isobutyl diethanolamino4-phenylbenzylamino t-butylacetate diethanolamino 4-phenylbenzylaminoMethylacetate diethanolamino 4-phenylbenzylamino Cyclobutyldiethanolamino 4-phenylbenzylamino Ethyl diethanolamino4-phenylbenzylamino Propyl diethanolamino

EXAMPLE 7

[0123] Composition of this invention were evaluated in the followingassays.

[0124] CDK2 assays:

[0125] Compositions of this invention were assayed to determine theirCDK2 inhibitory activity. The assay system (total volume of 50 μl)contained 50 mM Tris-Cl, pH 7.4, 10 mM MgCl₂, 5 mM DTT, 1 μg of histoneH1, 30 μM ATP (1 μCi of gamma ³²P labeled ATP), 10 1μg of BSA and 1 ngof purified CDK2. After incubation at 30° C. for 30 min, the reactionwas terminated by the addition of 10 μl of 10% TCA and the samples wereblotted onto to nitrocellulose filters. These filters were washedextensively in 10% TCA and assayed for radioactivity. Blanks containedno enzyme. To ascertain the potency of various compounds of thisinvention, the compounds were added to the above assay at concentrationsranging from 100 to 0.02 μg/ml. After incubation at 30 min., the assaytubes were processed as above. In all assays, various concentrations ofolomoucine were added and were used as a standard positive control. TheIC₅₀ (enzyme) listed in Table 7 is defined as the concentration requiredto inhibit CDK2 activity by 50%.

EXAMPLE 8 Cell Proliferation Assays:

[0126] Early passage rat aortic smooth muscle cells (CV TherapeuticsCell repository) were seeded in 48 well dishes (Falcon, ml/well) at adensity of 20,000 cells/ml of DME containing 5% heat inactivated bovineserum. The cells were incubated in a standard tissue culture incubatorfor 48 hr. The medium was aspirated and the wells were replenished with0.2 ml of fresh medium. Compounds of this invention were added atconcentrations ranging from 100 to 0.37 μg/ml. After 48 hr incubation,the medium was aspirated and the cultures were treated with 0.2 ml ofsaline 0.25 μl of phenozine methosulfate solution containing MTS (CellTiter 96® Aqueous Non-radioactive cell proliferation assay kit, Catalog# G 5430, Promega, 2800 Woods Hollow Road, Madison, Wis. 53711-5399).The IC₅₀ cells listed in Table 6 is defined as the concentrationrequired to inhibit cell proliferation by 50%. Olomoucine at variousconcentrations was added and was used as a standard positive control.TABLE 7 Bioactivity of Selected Representatives of this Invention IC₅₀(μg/ IC₅₀ mL) (μg/ en- mL) R₁′-X R2 R3 zyme cells benzylamino MeEthanolamino 7 70 4-methoxybenzylamino H Cl 60 NA 4-methoxyhenzylaminoMe Cl 6 >70 4-methoxybenzylamino Me Ethanolamino 4 48 4-chlorobenzyloxyH Cl 60 NA 4-chlorobenzyloxy Me Cl 60 NA 4-chlorobenzyloxytrifluoromethyl Cl >60 NA 4-methoxybenzylamino isopropyl Cl 4 774-methoxybenzylamino isopropyl Ethanolamino 4 43 4-methoxybenzylamino MeDiethanol- 4 48 amino 4-methoxybenzylamino 2-methylpropyl Cl 60 >70ethanolamino Me Ethanolamino >60 >70 4-methoxybenzylaminotrifluoromethyl Cl >60 >70 4-methoxybenzylamino benzyl Cl >60 >70ethanolamino H Benzylamino >60 NA 4-methoxybenzylamino isopropylDiethanol- 0.2 2.1 amino 4-methoxybenzylamino perfluoro- Cl >45 NAisopropyl 4-methoxybenzylamino perfluoro- Diethanol- 40 NA isopropylamino 4-methoxybenzylamino ispropyl 3-pyrroline 1 12.54-methoxybenzylamino hydroxyethyl Diethanol- 0.5 62 amino4-methoxybenzylamino isopropyl Serinol 0.4 15 4-methoxybenzylaminoisopropyl 1,3-diamino-2- 0.6 25 hydroxy- propane 4-methoxybenzylamino3-cyanopropyl Cl >60 NA 4-methoxybenzylamino 3-chloropropyl Cl >60 NA4-methoxybenzylamino benzyl Cl >60 NA 4-methoxybenzylamino Methyl 4-Cl >60 NA carboxybenzyl 4-methoxybenzylamino Naphthaloyl- Cl >60 NAethyl 4-chlorobenzylamino Trifluoro- Cl 1 NA methyl 4-methoxybenzylaminoisopropyl N-(2-cyano- 1 NA propyl) N-(3- pyridylmethyl)- amino4-methoxybenzylamino isopropyl 2-(hydroxy- 1 NA methyl)- 3-methylbutan-2-amino 4-methoxybenzylamino isopropyl 3 1 NA hydroxypiperi- dinocyclohexylmethylamino isopropyl Cl 1 NA piperonylamino isopropylDiethanol- 0.8 NA amino 4-methoxybenzylamino isopropyl Diisopropanol-0.8 NA amino anilino isopropyl Cl 1 NA 4-methoxybenzylamino isopropylN-benzyl-N-2- 1 NA hydroxyethyl- amino 4-phenylanilino isopropylDiethanol- 0.6 NA amino 4-phenylbenzylamino isopropyl Diethanol- 0.6 NAamino 4-phenylbenzylamino isopropyl 3-amino-1,2- 0.6 NA propanediol4-(2- isopropyl Diethannol- 0.5 NA thiophenyl)-benzylamino amino4-(4-methylphenyl) isopropyl Diethanol- 0.6 NA benzylamino amino 4-(4-isopropyl Diethanol- 0.6 NA trifluoromethylphenyl) amino benzyalmino4-thiomethoxyanilino isopropyl Cl 0.6 NA 3-(4-nitrilophenyl) isopropylDiethanol- 0.5 NA anilino amino 3-thiomethoxyanilino isopropylDiethanol- 0.1 NA amino 4-thiomethoxyanilino isopropyl Diethanol- 0.07NA amino 3-methoxybenzylamino isopropyl Cl 0.9 NA 4-(2-pyridinyl)isopropyl Diethanol- 0.16 NA benzylamino amino 3-methoxybenzylaminoisopropyl Diethanol- 0.5 NA amino (4- Isopropyl Diethanol- 0.12 0.3Chlorophenyl)- amino methylamino (4- Isopropyl Diethanol- 0.15 2.2Fluorophenyl)- amino methylamino (4- Isobutyl Diethanol- 59 NATrifluoromethylphenyl) amino methylamino (4- Isopropyl Diethanol- 0.56NA Trifluoromethylphenyl) amino methylamino (4- Isopropyl (S)-2-Amino-3-1.07 NA Chlorophenyl)- phenylpropyl- methylamino amino (4- Isopropyl 2-0.17 1.4 Fluorophenyl)- Aminoethyl- methylamino amino (4- Isopropyl(D)-1- 0.06 2.7 Fluorophenyl)- Hydroxy- methylamino methyl- 2-methylpropylamino (4-Fluorophenyl)- Isopropyl (L)-1- 0.19 NA methylaminoHydroxy- methyl-2- propylamino (4- Isopropyl (D)-1- 0.19 NAChlorophenyl)- Hydroxy- methylamino methyl-2- methyl propylamino (4-Isopropyl (L)-1- 0.05 NA Chlorophenyl)- Hydroxy- methylamino methyl-2-methyl- propylamino (4- Isopropyl 2-Hydroxy-2- 0.08 >5 Chlorophenyl)-phenyl- methylamino ethylamino (4- Isopropyl 2-Amino-N1- 0.07 0.2Chlorophenyl)- (2-hydroxy methylamino ethyl) ethylamino (4- Isopropyl2-Amino-N2- 2.02 NA Chlorophenyl)- (2-hydroxy- methylamino ethyl)ethylamino (4- Isopropyl (S)-2-Phenyl-1- 1.07 NA Chlorophenyl)-carboxamido- methylamino ethylamino (4- Isopropyl 2-Amino-N2- 0.43 NAChlorophenyl)- (2-hydroxy- methylamino ethyl)-N1- (hydroxy- ethyl)-ethyl amino (4- Isopropyl 2- 9 NA Sulfonamidophenyl)- Aminoethyl-methylamino amino (4- 2-Oxo-3-butyl Diethanol- 11 NA Fluorophenyl)-amino methylamino (4- 2-Oxo-3-butyl Diethanol- 37 NA Chlorophenyl)-amino methylamino (4- Isopropyl 2- 0.35 0.1 Chlorophenyl)- Aminoethyl-methylamino amino (4- Isopropyl 3- 1.0 NA Chlorophenyl)- Aminopropyl-methylamino amino (4- Isopropyl 5- 31 NA Chlorophenyl)- Aminopentyl-methylamino amino (4- Isopropyl 2-Amino- 0.05 0.1 Chlorophenyl)-2-methyl- methylamino ethylamino (4- Isopropyl (S)-(+)-1- 0.17 NAChlorophenyl)- (Hydroxy- methylamino methyl)- propylamino (4- Isopropyl(R)-(−)-1- 0.18 NA Chlorophenyl)- (Hydroxy- methylamino methyl)-propylamino (4- Isopropyl (S)-(+)-1- 0.26 NA Chlorophenyl)- (Hydroxyl-methylamino methyl)- ethylamino (4- Isopropyl (R)-(−)-1- 0.35 NAChlorophenyl)- (Hydroxy- methylamino methyl)- ethylamino (4- Isopropyl(S)-(+)-2- 0.38 NA Chlorophenyl)- Hydroxy- methylamino propyl amino (4-Isopropyl (R)-(−)-2- 0.43 NA Chlorophenyl)- Hydroxy- methylamino propyl-amino (4- Isopropyl 2-Amino- 0.48 NA Fluorophenyl)- propylaminomethylamino (4- Isopropyl (S)-(2- 0.63 NA Fluorophenyl)- Tetrahydro-methylamino furanyl)- methylamino (4- Isopropyl (R)-(2- 0.58 NAFluorophenyl)- Tetrahydro- methylamino furanyl) (4- Isopropyl2-Hydroxy-1- 0.18 NA Fluorophenyl)- methylethyl- methylamino amino (4-Isopropyl (S)-2-Hydroxy- 0.22 NA Fluorophenyl)- 2-methylethyl-methylamino amino (4- Isopropyl (R)-2-Hydroxy- 0.23 >5 Fluorophenyl)-2-methylethyl- methylamino amino (4- Isopropyl 1- 0.11 2.4Fluorophenyl)- Hydroxy- methyl- methylamino propylamino

[0127] The inhibition of cell proliferation properties of the compoundsof this invention are demonstrated by their ability to inhibit cellproliferation in the range of about 0.05 μg/ml to 100 μg/ml, preferablyless than 0.5 μg/ml.

[0128] Similar assays were performed using the following cell lines;P388 —mouse lymphoid neoplasm; L1210 —mouse lymphcytic leukemia; Caco2human colon adenocarcinoma; MCF7 human breast adenocarcinoma; PupVSMCrat neonatal aortic smooth muscle cells; Ovcar human ovarian Carcinoma;Panc1 human pancreatic adenocarcinoma; and HUVEC human umbilical cordendothelial cells. The inhibitory activity of several compositions ofthis invention against one or more of the cell lines are reported inTables 8 and 9 below. TABLE 8 IC₅₀ (μg/ml) for Inhibition of CellProliferation Pup HU P L Caco MCF OvC VS VE R₁X R₂ R₃ 388 120 2 7 Panc1ar MC C (4- Isopropyl Diethanolamino 1.5 2.5 4.5 8.0 10.0 11.0 0.5 3.0methoxyphenyl)- methylamino (4- Isopropyl Diethanolamino 1.0 4.0 0.5 4.04.0 7.0 1.0 phenylphenyl)- amino (4- Isopropyl Diethanolamino <1.0 1.03.5 1.0 1.3 2.0 phenylphenyl)- methylamino (4- Isopropyl Morpholino >55.5 4.0 methoxyphenyl)- methylamino 3-phenoxyphenyl, isopropylDiethanolamino 1.5 2.0 2.5 2.0 3-benzyloxyphenyl

[0129] TABLE 9 R₁X R₂ R₃ MRC-5 PupVSMC (4-methoxyphenyl)- IsopropylDiethanolamino 5 0.4 methylamino 4-Chlorophenyl)- Isopropyl2-Aminoethyl- 1 0.1 methylamino amino (4-Chlorophenyl) Isopropyl2-Amino-2- 1 0.1 methylamino methylethylamino (4-Chlorophenyl)-Isopropyl 2-Amino-N1-(2- 1 0.3 methylamino hydroxyethyl) ethylamino(4-Chlorophenyl)- Isopropyl Diethanolamino 3 0.3 ethylamino

EXAMPLE 8

[0130] Compounda of this invention was evaluated for effectiveness usingthe Murine Leukemia Model. The Murine Leukemia Model is a standard modelused in the evaluation of antitumor agents. CDF1 mice were injected ipwith L1210 cells (1×10³ cells/mouse). Twenty-four hours later, thesemice were treated with various doses (ip) of compound 3 of Example 1 insaline. The dosing regimen used in this study is outlined in Table 10,below. Mice were dosed with compound 3 daily or on alternate days.Control mice received saline. After 7 days, dosing was suspended andsurvival monitored. TABLE 10 Median survival time Treatment N Days T/C ×100 Saline control 7 10 (9-13) 100 Compound 3 0.5 mg/kg bid 7 11 (10-15)110 1.0 mg/kg bid 7 13 (11-13) 130 2 mg/kg bid 7 12 (10-14) 120 4mg/kg-days 7 13 (10-15) 130 1, 3, 5, 7 8 mg/kg-days 7 13 (12-16) 130 1,3, 5, 7

[0131] The results indicate that rats administered compound 3 survivedlonger than the control rats.

EXAMPLE 9

[0132] This example measured the effect of an acute local delivery ofcompound 3 of Example 1 in reducing neointima formation followingballoon angioplasty in the rat carotid artery model. In this example,the left common carotid arteries of adult male rats (n=10 perexperimental group) were surgically injured using a Fogarty arterialembolectomy catheter. Immediately after injury, the common carotidartery was bisected with a vascular clamp, thereby establishing anuntreated and treated segment. A drug delivery catheter was theninserted into the distal half of the common carotid. After drugdelivery, the catheter was removed and excess drug was washed out byremoving the vascular clamp and re-establishing blood flow beforeclosing the artery. The animals were allowed to recover for 14 daysbefore harvesting the common carotid artery. The harvested tissue wassectioned and the neointimal area was digitized and measured with acomputer planimetery system. For each animal, 15 measurements wereaveraged for the untreated segment and 15 for the treated.{2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]aminewas administered at a dose of 5 mg/mL reducing the neointimal area about90% in comparison to the 6% reduction of saline alone.

[0133] The results of this Example are found in FIG. 1. According toFIG. 1, administering compound 3 of Example 1 to a damaged carotidartery reduced the neointimal area about 88% in comparison to the 6%reduction produced by the saline vehicle alone.

EXAMPLE 10 IκB-α Kinase Assays:

[0134] Compositions of this invention were assayed to determine theirIκB-α kinase inhibitory activity. The human umbilical vein endothelialcell line (HUVEC) used in these studies was purchased from Clonetics(San Diego, Calif.) and was maintained in endothelial cell growth mediumsupplemented with 2% fetal bovine serum, 10 ng/ml human recombinantepidermal growth factor, 1 μg/ml hydrocortisone, 50 μg/ml gentamicin, 50ng/ml amphotericin B and 12 μg/ml bovine brain extract at 37° C. in atissue culture incubator. All growth media and supplements werepurchased from Clonetics (San Diego, Calif.). E. coli lipopolysaccharide(LPS) serotype 0111:B4 was purchased from Sigma (Saint Louis, Mich.).All other chemicals were of reagent grade.

[0135] Preparation of cell Lysate: Monolayers (75 cm²) of HUVEC cellswere treated with LPS (100 ng/ml) for 5 minutes after which the cellmedia was rapidly removed and the monolayer washed three times with icecold PBS. The cell layer was scraped into 10 ml PBS and the cellspelleted by centrifugation (3000 rpm, 5 min, 4° C.). Cell lysate wasprepared by incubating the cell pellet in 0.2 ml lysis buffer (20 mMHEPES, pH7.3, 50 mM NaCl, 10 mM MgCl₂, 1 mM EDTA, 1 mM EGTA, 1 mM sodiumorthovanadate, 10 mM β-glycerophospate, 1 mMphenylmethylsulfonylfuoride, 1 mM dithiothreitol, 0.5% Nonidet P-40 for15 minutes at 37° C. for frequent vortexing. Cell debris was removedfrom the sample by microcentrifugation (10,000 xg, 15 minutes, 4° C.)and the supernatant was “precleared” by the addition of 100 ml of asuspension of sepharose 4B in lysis buffer and mixing gently for 1 hourat 4° C. The speharose 4B beads were removed by microcentrifugation andthe supernatant aliquotted and stored at 80° C.

[0136] Solid Phase IκB-α kinase assay: 1 μg of GST- IκB-α, correspondingto full length IκB-α of human origin, (Santa Cruz Biotechnology,) wasincubated with 20 μl of a 50% slurry of glutathione S sepharose 4B(Pharmacia) in reaction buffer (20 mM HEPES, pH7.3, 10 mM MgCl₂, 15 mMβ-glycerophosphate, 0.5 mM sodium orthovanadate, 0.5 mM EGTA) for 30minutes at room temperature. The GST- IκB-bead complex was the washedthree times with 0.5 ml of reaction buffer by resuspension andmicrocentrifugation. 10μg of HUVEC cell lysate protein in 100 μl ofreaction buffer was then added to the GST- IκB-bead complex and themixture incubated with gentle mixing at 4° C. for 1 hour. The beadcomplex was then washed three times with reaction buffer containing 0.2M NaCl and once with reaction buffer alone. Finally the bead complex wasresuspended in 20μl of reaction buffer containing 5 μCi [y-³²P]ATP(>5000 ci/mmol, New England Nuclear Corp. Boston, Mass.) and incubatedat room temperature for 15 minutes. The reaction was terminated by theaddition of 10 μl of SDS-PAGE sample buffer and boiled for 3 minutesbefore separation by SDS-PAGE (10-20% gradient Readygel, BioRad).Following electrophoresis the gel was fixed (50% methanol 10% aceticacid) for 15 minutes, washed three times for 5 minutes each withdistilled H₂O and treated with 5% glycerol for 15 minutes before dryingdown and exposing to film for autoradiography (X-OMAT XAR-5 Kodak).

[0137] In gel kinase assay: IκB-α isozymes were assayed for activityusing a modification of previously published methods (11, 19, 20).Briefly duplicate samples of the IκB-glutathione sepharose 4B beadcomplex were prepared as described above and were separated byelectrophoresis through a 12% SDS-PAGE gel which had been polymerised inthe presence of 15 μg/ml GST-IκB-α. Following electrophoresis the gelwas washed gently twice for 30 minutes each with 50 mM Tris-HCI pH8.0, 5mM β-mercaptoethanol; 20% isopropanol to remove SDS. Proteins were thendenatured within the gel by incubation for 45 minutes in 100ml 50mMTris-HCI pH8.0; 5 mM β-mercaptoethanol; 0.04% Tween 40. The gel was thencut in half to separate the duplicate samples, one half was incubated in10 ml reaction buffer alone and the other in 10 ml reaction buffercontaining 10 μg/ml of 2-diethanolamino-6(4-phenyl anilino)-9-isopropylpurine (compound 6 of Example 2) for 1 hour at room temperature which 10μCi[y-³²P]ATP was added and the incubations continued for a further hourat room temperature. The gels were then subjected to multiple 15 minutewashes of 100ml each 5% trichloroacetic acid containing 1% sodiumpyrophosphate until 1 ml of wash solution gave close to backgroundradioactivity. The gels were then dried down and exposed to file forautoradiograhy.

[0138] Preparation of2-diethanolamino-6-(4-phenybenzylamino)-9-isopropyl purine Epoxyactivated Senharose 6B Affinity Matrix. Freeze dried epoxy activatedSepharose 6B (Pharmacia LKB, Piscataway, N.J.) was chosen for thecoupling reaction due to its ability to form an ether bond between anhydroxyl-containing ligand and the epoxide group on the sepharose. Thegel was swollen according to the manufacturer's instructions, (100 mg)of compound 6 of Example 2 was dissolved in 1 ml coupling solution(1.2:1 v/v dimethylformamide : 0.1N NaOH) and mixed with 0.5 ml ofswollen gel at pH 10-11 for 72 hours at room temperature with gentleagitation. Excess reactive groups were blocked with 1M ethanolamine for4 hours at 50° C. and the gel slurry was poured into 1 ml syringecolumn. The resin was activated with three alternating cycles of twentycolumn volumes each of pH 4.0 (0.1M acetate, 0.5M NaCl) and pH 8.0 (0.1MTris-HCl, 0.5M NaCl) buffers followed by twenty column volumes ofreaction buffer (20 mM HEPES, pH7.3, 10 MM MgCl₂, 15 mMβ-glycerophophate, 0.5 mM sodium orthovanadate, 0.5 mM EGTA). The columnwas stored at 4° C. in reaction buffer containing 0.5% sodium azide andregenerated prior to each use with alternating cycles of low and high pHas described above.

[0139] Activated HUVEC cell lysate (500 μg protein in 1 ml reactionbuffer) was passed over the CVT-1545 sepharose matrix sequentially fivetimes and the flow through was saved (unbound material). The matrix wasthen washed three times with 1 ml of reaction buffer (wash 1-3) thenthree times each with reaction buffer containing 0.5M NaCl (eluate 1-3).Aliquots (20 μl from 1 ml) of each sample were assayed for their abilityto phosphorylate at GST-IκB-sepharose bead complex and analyzed bySDS-PAGE as described above.

[0140] Assay of affinity enriched IκB-α kinase. The bulked 0.5 M NaCleluates from the affinity matrix were used as the source of enzyme fordevelopment of an IκB-α kinase filter assay. Each reaction containedaffinity enriched IκB-α kinase (1 μg protein), 10 ng GST IκB-α kinaseand 0.5 μCi[y-³²P]ATP (>5000 Ci/mmol, New England Nuclear Corp, Boston,Mass.) in 20 μl reaction buffer. The reaction was incubated for 15minutes at room temperature and was terminated by the addition of 2 μl0.5M EDTA. Reaction mixtures were blotted onto phosphocellulose disks(Gibco BRL Life Technologies, Gaithersburg, Md.) and the filters washedthree times with 0.15M phosphoric acid with gentle shaking for 15minutes (up to ten filters were washed with 300 ml of 0.15M phosphoricacid.) Following a third wash the filters were air dried, added toscintillation fluid and assayed by liquid scintillation spectrometry.

[0141] Electrophoretic Mobility Shift Assay: Nuclear extracts wereprepared using a high-salt buffer extraction procedure. 10 pmol ofdouble stranded NF-κB consenses oligonucleotide(5′-AGTTGAGGGGACTTTCCCAGGC-3′))Promega) was 5′end labeled with 5μCi[y-³²P]ATP (>5000 Ci/mmol, New England Nuclear Corp, Boston, Mass.) byincubaton with T4 polynucleotide kinase for 1 hr at 37° C.Unincorporated nucleotides were removed by pasing the reaction mixtureover 1 ml Sephadex G-5-spin column. Binding assays were performed atroom temperature for 1 hr and consisted of 10 μg nuclear extractprotein, 1 μg salmon sperm DNA, and 5×10⁴ cpm of ³²P labeled consensusof oligonucleotide in the presence and absence of fifty fold unlabeledoligonucleotide. DNA-protein complexes were resolved by 8% nondenaturing polyacrylamide gel electrophoresis, the gels were dried ontofilter paper and visualized by autoradiography. TABLE 11 Enzyme Activityof Selected Representatives of this Invention IC50 (μM) R₁′-X R2 R3enzyme 4-phenylbenzylamino Isopropyl Diethanolamino 1.14-phenylbenzylamino Isopropyl Diethylamino >2.4 4-phenylbenzylaminoIsopropyl Ethanolamino 2.5 4-bromoanilino Isopropyl Diethanolamino 144-(3-methoxphenyl)- Isopropyl Diethanolamino >10 benzylamino4-(4-methoxphenyl)- Isopropyl Diethanolamino 11 benzylamino3-(4-nitrilophenyl)- Isopropyl Diethanolamino 2.2 amino4-thiomethoxyanilino Isopropyl Diethanolamino 12.4 4-(2-pyridinyl)Isopropyl Diethanolamino 4.5 benzylamino

What we claim is:
 1. A 2,6,9-trisubstituted purine composition of matterhaving the following formula:

wherein R₁ is halogen or R′₁-X wherein X═NH, O, S, S(O₂). R′ is alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylaikyl, alkenyl, andaikynyl, each having one to 20 carbon atoms, which alkyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkyyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, CF₃, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹,SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³,OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ andCOR²⁰; R₂ is a hydrogen or hydrocarbon selected from the group alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl,andalkynyl, each having one to 20 carbon atoms, which alkyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, SO₂NR²⁰COR²¹,SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰ CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰, OCONR²⁰R²³,OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, C₂R²⁰, CONR²⁰R²³, CONR²⁰SO₂R²¹ and COR²⁰;R₃ is a halogen, hydroxyl, thio, alkoxy, alkylthio, alkyl, —NR₄R₅ or acomponent having the formula:

where m=1-3, n=1-3, o=1,3, y=carbonyl, —NR₄R₅, hydroxyl, thiol, alkoxy,alkylthiol; R₄ and R₅ are each independently hydrogen, OR₂₀, NR₂₀R₂₃, ora hydrocarbon selected from the group including alkyl, acyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, each having one to 20 carbon atoms, which alkyl, acyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, aryl,heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³,SO₂NR²⁰COR²¹, SO₂NR²⁰CONR²⁰R²³, SO₂NR²⁰CO₂R²¹, NR²⁰R²³, NR²⁰COR²¹,NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³, N(R²⁰)C(NR²⁰)NHR²³, NR²⁰SO₂R²¹, OR²⁰,OCONR²⁰R²³, OCONR²⁰SO₂R²¹, OCONR²⁰R²³, CN, CO₂R²⁰, CONR²⁰R²³,CONR²⁰SO₂R²¹ and COR²⁰; with the proviso that when Y is carbonyl, Y andR′₄ together may be a single oxygen atom, R₄″ and R₅″ together may be asingle oxygen atom, R₄′″ and R₅′″ may together be a single oxygen atom,and wherein when R₃ is 2-hydroxyethylamino and R₂ is methyl, R₁′-X isnot amino, 3-methyl-2-butenylamino, benzylamino, orm-hydroxybenzylamino, when R₃ is not 2-hydroxyethylamino, when R₂ isisopropyl, R₁′-X is not benzylamino, m-hydroxybenzylamino, or3-methylbutylamino, when R₃ is 2-hydroxyethylamino and R₂ is2-hydroxyethyl, R₁′-X is not benzylamino and when R₃ is selected fromthe group consisting of 2-methyl-2-hydroxypropylamino, and2-dimethylaminoethylamino, and when R₂ is methyl, then R₁′-X is notbenzylamino; R²⁰ is a member selected from the group consisting of H,C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, andheteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl;R²¹ is a member selected from the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl,alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionallysubstituted with 1 to 3 substituents independently selected from thegroup of halo, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OR²⁰, OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, andOCON(R²⁰)₂, and each optional heteroaryl, aryl, and heterocyclylsubstituent is optionally substituted with halo, alkyl, CF₃, amino,mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR²²,NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰,OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R²² is amember selected from the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl,C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl,alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substitutedwith 1 to 3 substituents independently selected from halo, alkyl, mono-or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆ alkyl,CF₃, aryl, and heteroaryl; and R²³ is R²¹ or H.
 2. A2,6,9-trisubstituted purine composition of claim 1 wherein: R′₁ is aalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, CF₃, aryl,heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³,NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³, NR²⁰SO₂R²¹, OR²⁰, CN,CO₂R²⁰, CONR²⁰R²³, and COR²⁰; R₂ is a hydrogen or hydrocarbon selectedfrom the group substituted alkyl, heterocyclyl, aryl, heteroaryl,aralkyl, heteroarylalkyl, alkenyl, and alkynyl, each having one to 20carbon atoms, which alkyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹,SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³,NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, CONR²⁰R²³, and COR²⁰; R₄ and R₅ are eachindependently hydrogen, OR₂₀, NR₂₀R₂₃, or a hydrocarbon selected fromthe group including alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, heteroarylalkyl, alkenyl, and alkynyl, each having one to 20carbon atoms, which alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, heteroarylalkyl, alkenyl, and alkynyl, are optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of halo, aryl, heteroaryl, heterocyclyl, R²², SR²⁰,S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹,NR²⁰CONR²⁰R²³, NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, CONR²⁰R²³, and COR²⁰; R²⁰is a member selected from the group consisting of H, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₁₅ heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with I to3 substituents independently selected from halo, alkyl, mono- ordialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃,aryl, and heteroaryl; R²¹ is a member selected from the group consistingof C₁₋₈ alkyl, C₂₋₈ alkenyl, heterocyclyl, aryl, and heteroaryl, whichalkyl, alkenyl, aryl, heterocyclyl, and heteroaryl are optionallysubstituted with 1 to 3 substituents independently selected from thegroup of halo, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OR²⁰, OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, andOCON(R²⁰)₂, and each optional heteroaryl, aryl, and heterocyclylsubstituent is optionally substituted with halo, alkyl, CF₃, amino,mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR²²,NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰,OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; and R²² isa member selected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl,heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl.3. A 2,6,9-trisubstituted purine composition of claim 1 wherein: R′₁ isalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, CF₃, aryl,heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³,NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, N²⁰SO₂₁, OR²⁰, CN, CO₂R²⁰, CONR²⁰R²³,and COR²⁰; R₂ is a hydrogen or hydrocarbon selected from the groupincluding alkyl, heterocyclyl, and aryl, each having one to 10 carbonatoms, which alkyl, heterocyclyl, aryl, are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹,SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰,CN, CO₂R²⁰, CONR²⁰R²³, and COR²⁰; R₄ and R₅ are each independentlyhydrogen, OR₂₀, NR₂₀R₂₃, or a hydrocarbon selected from the groupincluding alkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkenyl,and alkynyl, each having one to 20 carbon atoms, which alkyl, acyl,heterocyclyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl, areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl,heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³,NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, CONR²⁰R²³, andCOR²⁰; R²⁰ is a member selected from the group consisting of H, C₁₋₈alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroarylamide, CN, O—C₁₋₆ alkyl, CF₃; R²¹ is a member selected from the groupconsisting of C₁₋₈ alkyl, aryl, and heteroaryl, which alkyl, aryl, andheteroaryl are optionally substituted with 1 to 2 substituentsindependently selected from the group of halo, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, NR²⁰SO₂R²², OR²⁰; and R²² is a member selected fromthe group consisting of C₁₋₈ alkyl, aryl, and heteroaryl, which alkyl,aryl, and heteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl.4. A 2,6,9-trisubstituted purine composition of claim 1 wherein: R′₁ isa alkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, andalkynyl, are optionally with from 1 to 2 substituents independentlyselected from the group consisting of halo, CF₃, aryl, R²², SR²⁰,S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹,OR²⁰, CN, CO₂R²⁰, and CONR²⁰R²³; R₂ is a hydrogen or hydrocarbonselected from the group alkyl, heterocyclyl, and aryl, each having oneto 10 carbon atoms, which alkyl, heterocyclyl, aryl, are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, aryl, heteroaryl, heterocyclyl, R²², SR²⁰,S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹,OR²⁰,CN, CO₂R²⁰, CONR²⁰R²³, and COR²⁰; R₄ and R₅ are each independentlyhydrogen, or a hydrocarbon selected from the group including alkyl,acyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl,each having one to 20 carbon atoms, which alkyl, acyl, heterocyclyl,aryl, heteroaryl, aralkyl, alkenyl, and alkynyl, are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, aryl, R²², SR²⁰, S(O)R²¹, SO₂R²¹,SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰, CN,CO₂R²⁰, and CONR²⁰R²³; R²⁰ is a member selected from the groupconsisting of H, C₁₋₈ alkyl, aryl, and heteroaryl, which alkyl, aryl,and heteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃; R² is a member selectedfrom the group consisting of C₁₋₈ alkyl, aryl, and heteroaryl, whichalkyl, aryl, and heteroaryl are optionally substituted with 1 to 2substituents independently selected from the group of halo, CF₃, CN,OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²²,NR²⁰CON(R²⁰)₂, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰SO₂R²², OR²⁰; and R²² is amember selected from the group consisting of C₁₋₈ alkyl, aryl, andheteroaryl, which alkyl, aryl, and heteroaryl are optionally substitutedwith 1 to 3 substituents independently selected from halo, alkyl, mono-or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆ alkyl,CF₃, aryl, and heteroaryl.
 5. The 2,6,9-trisubstituted purinecomposition of claim 1 wherein X═NH.
 6. The 2,6,9-trisubstituted purinecomposition of claim 1 wherein R₃ is a component having the formula:

where m=1-3, n=1-3, o=1,3, y=carbonyl, —NR₄R_(5,) hydroxyl, thiol,alkoxy, alkylthiol with the provisos that when Y is carbonyl, Y and R′₄together may be a single oxygen atom, R₄″ and R₅″ may together be asingle oxygen atom, R₄′″ and R₅′″ may together be a single oxygen atom;and R₄ and R₅ are each independently hydrogen, or a hydrocarbon selectedfrom the group including alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, alkenyl, and alkynyl, each having one to 20 carbon atoms, whichalkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, aryl, R²²,SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹, NR²⁰COR²¹,NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, and CONR²⁰R²³.
 7. The 2,6,9-trisubstitutedpurine composition of claim 3 wherein R₁′ is selected from the groupconsisting of aralkyl and heteroarylalkyl.
 8. The 2,6,9-trisubstitutedpurine composition of claim 7 wherein R₁′ is selected from the groupconsisting of aralkyl, unsubstituted pyridylalkyl and substitutedpyridylalkyl and wherein R₂ is selected from the group consisting oflower alkyl, substituted lower alkyl, and alkyl cycloalkyl.
 9. A2,6,9-trisubstituted purine composition of claim 5 wherein: R′₁ is anaryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, each havingone to 20 carbon atoms, which aryl, heteroaryl, heterocyclyl, aralkyl,heteroarylalkyl, are optionally substituted with from 1 to 2substituents independently selected from the group consisting of halo,CF₃, aryl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³, NR²⁰R²³, NR²⁰COR²¹,NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰ , CN, CO₂R²⁰, and CONR²⁰R²³; R₂ is ahydrogen or hydrocarbon selected from the group substituted lower alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl each having one to10 carbon atoms wherein substitution includes optional substitution withfrom 1 to 2 substituents independently selected from the groupconsisting of halo, R²², SR²⁰, S(O)R²¹, SO₂R²¹, NR²⁰R²³, OR²⁰, and CN;R₄ and R₅ are each independently hydrogen, or a hydrocarbon selectedfrom the group including alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, alkenyl, and alkynyl, each having one to 20 carbon atoms, whichalkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkenyl, andalkynyl, are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, aryl, R²²,SR²⁰, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, andCONR²⁰R²³; R²⁰ is a member selected from the group consisting of H, C₁₋₈alkyl, which alkyl is optionally substituted with 1 to 2 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl orCN, O—C₁₋₆ alkyl, CF₃; R²¹ is a member selected from the groupconsisting of C₁₋₈ alkyl, which alkyl is optionally substituted with 1to 2 substituents independently selected from the group of halo, CF₃,CN, OR²⁰, SR²⁰, N(R²⁰)₂; and R² is a member selected from the groupconsisting of C₁₋₃ alkyl, aryl, heteroaryl which alkyl, aryl, andheteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl, CN, O—C₁₋₆ alkyl, CF₃.
 10. The 2,6,9-trisubstituted purinecomposition of claim 3 wherein R₁′ is selected from the group consistingof aryl, heterocyclyl, heteroaryl, substituted heteroaryl, andsubstituted aryl.
 11. The 2,6,9-trisubstituted purine composition ofclaim 3 wherein R₁′ is selected from the group consisting of aryl,unsubstituted pyridyl, substituted pyridyl, and substituted aryl, and R₂is selected from the group consisting of alkyl, substituted alkyl. 12.The 2,6,9-trisubstituted purine composition of claim 2 wherein R₃ is—NR₄R₅ wherein R₄ and R₅ are each selected from the group consisting ofhydrogen, alkyl, heterocyclyl, acyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkyl alkenyl, alkyl alkynyl, each having one to 20carbon atoms, which alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, heteroarylalkyl, are optionally substituted with from 1 to 3substituents independently selected from the group consisting of halo,aryl, heteroaryl, heterocyclyl, R²², SR²⁰, S(O)R²¹, SO₂R²¹, SO₂NR²⁰R²³,NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰CONR²⁰R²³, NR²⁰SO₂R²¹, OR²⁰, CN,CO₂R²⁰, CONR²⁰R²³, and COR₂₀.
 13. A 2,6,9-trisubstituted purinecomposition of claim 12 wherein: R′₁ is an aryl, substituted aryl, eachhaving 6 carbon atoms wherein substitution includes optionalsubstitution with from 1 to 2 substituents independently selected fromthe group consisting of halo, CF₃, aryl, R²², NR²⁰R²³, NR²⁰COR²¹, OR²⁰,CN; R₂ is a hydrogen or hydrocarbon selected from the group substitutedlower alkyl, cycloalkyl, substituted cycloalkyl each having one to 6carbon atoms wherein substitution includes optional substitution withfrom 1 to 2 substituents independently selected from the groupconsisting of halo, R²², NR²⁰R²³, OR²⁰; R₄ and R₅ are each independentlyhydrogen, or a hydrocarbon selected from the group including alkyl, andheterocyclyl wherein each hydrocarbon has from 1 to 12 carbon atoms,which alkyl, and heterocyclyl are optionally substituted with from 1 to2 substituents independently selected from the group consisting of halo,R²², SR²⁰, OR²⁰, NR²⁰R²³, CN, CO₂R²⁰, and CONR²⁰R²³; R²⁰ is a memberselected from the group consisting of H, C₁₋₈ alkyl; R²¹ is a memberselected from the group consisting of C₁₋₃ alkyl, which alkyl isoptionally substituted with 1 to 2 substituents independently selectedfrom the group of halo, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂; and R²² is amember selected from the group consisting of C₁₋₃ alkyl, aryl,heteroaryl which alkyl, aryl, and heteroaryl are optionally substitutedwith 1 to 3 substituents independently selected from halo, alkyl, mono-or dialkylamino, alkyl or aryl, CN, O—C₁₋₆ alkyl, CF₃.
 14. A2,6,9-trisubstituted purine composition of claim 12 wherein: R′₁ is anaryl, substituted aryl, each having 6 carbon atoms wherein substitutionincludes optional substitution with from 1 to 2 substituentsindependently selected from the group consisting of halo, CF₃, R²²,OR²⁰, CN; R₂ is isopropyl; R₄ and R₅ are each independently hydrogen, ora hydrocarbon selected from the group including alkyl, and heterocyclylwherein each hydrocarbon has from 1 to 12 carbon atoms, which alkyl, andheterocyclyl are optionally substituted with from 1 substituentindependently selected from the group consisting of R²², OR²⁰, NRR²³;R²⁰ is a member selected from the group consisting of H, C₁₋₂ alkyl; R²¹is a member selected from the group consisting of C₁₋₃ alkyl; R²² is amember selected from the group consisting of C₁₋₃ alkyl, aryl, whichalkyl, aryl, are optionally substituted with 1 substituent independentlyselected from halo, alkyl, mono- or dialkylamino, CN, CF₃; and R²³ isR²¹ or H.
 15. A 2,6,9-trisubstituted purine composition of claim 12wherein: R′₁ is an aralkyl, substituted aralkyl, each having 6-8 carbonatoms wherein substitution includes optional substitution with from 1 to2 substituents independently selected from the group consisting of halo,CF₃, aryl, R²², NR²⁰R²³, NR²⁰COR²¹, OR²⁰, CN; R₂ is a hydrogen orhydrocarbon selected from the group substituted alkyl, cycloalkyl,substituted cycloalkyl each having one to 6 carbon atoms whereinsubstitution includes optional substitution with from I substituentindependently selected from the group consisting of halo, R²², NR²⁰R²³,OR²⁰; R₄ and R₅ are each independently hydrogen, or a hydrocarbonselected from the group including alkyl and heterocyclyl wherein eachhydrocarbon has from 1 to 12 carbon atoms, which alkyl and heterocyclylare optionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of halo, R²², SR²⁰, OR²⁰, NR²⁰R²³,CN, CO₂R²⁰, and CONR²⁰R²; R²⁰ is a member selected from the groupconsisting of H, C₁₋₈ alkyl; R²¹ is a member selected from the groupconsisting of C₁₋₃ alkyl, which alkyl is optionally substituted with 1to 2 substituents independently selected from the group of halo, CF₃,CN, OR²⁰, SR²⁰, N(R²⁰)₂; and R²² is a member selected from the groupconsisting of C₁₋ ₃alkyl, aryl, heteroaryl which alkyl, aryl, andheteroaryl are optionally substituted with 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl, CN, O—C₁₋₆ alkyl, CF₃.
 16. A 2,6,9-trisubstituted purinecomposition of claim 12 wherein: R′₁ is —CH₂-phenyl wherein the phenylring is optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, CF₃, R²²,OR²⁰, CN; R₂ is isopropyl; R₄ and R₅ are each independently hydrogen, ora hydrocarbon selected from the group including alkyl, and heterocyclylwherein each hydrocarbon has from 1 to 12 carbon atoms, which alkyl, andheterocyclyl are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of R²², OR²⁰, NR²⁰R²³;R²⁰ is a member selected from the group consisting of H, C₁₋₂ alkyl; R²¹is a member selected from the group consisting of C₁₋₃ alkyl; R²² is amember selected from the group consisting of C₁₋₃ alkyl, aryl, whichalkyl, aryl, are optionally substituted with 1 substituent independentlyselected from halo, alkyl, mono- or dialkylamino, CN, CF₃; and R²³ isR²¹ or H.
 17. The 2,6,9-trisubstituted purine composition of claim 12wherein R₁′ is selected from the group consisting of aralkyl,substituted pyridylalkyl, and unsubstituted pyridylalkyl; R₂ is selectedfrom the group consisting of alkyl, which alkyl is optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, R²², NR²⁰R²³, OR²⁰; R₄ is a substitutedalkyl having from 2 to 6 carbon atoms optionally substituted with from 1to 3 substituents independently selected from the group consisting ofR²², OR²⁰ NR²⁰R²³; R₅ is selected from the group consisting of hydrogen,alkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, each having one to20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, aryl, R²²,SR²⁰, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, andCONR²⁰R²³; R²⁰ is a member selected from the group consisting of H. C₁₋₂alkyl R²¹ is a member selected from the group consisting of C₁₋₃ alkyl;R²² is a member selected from the group consisting of C₁₋₃ alkyl, aryl,which alkyl, aryl, are optionally substituted with 1 substituentindependently selected from halo, alkyl, mono- or dialkylamino, CN, CF₃;and R²³ is R²¹ or H.
 18. The 2,6,9-trisubstituted purine composition ofclaim 12 wherein R₁′ is selected from the group consisting of aryl,substituted aryl, pyridyl, and substituted pyridyl; R₂ is selected fromthe group consisting of alkyl, which alkyl is optionally substitutedwith from 1 to 2 substituents independently selected from the groupconsisting of halo, R²², NR²⁰R²³, OR²⁰; R₄ is a substituted alkyl havingfrom 2 to 6 carbon atoms optionally substituted with from 1 to 3substituents independently selected from the group consisting of R²²,OR²⁰ , NR²⁰R²³; R₅ is selected from the group consisting of hydrogen,alkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, each having one to20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl, heteroaryl,aralkyl, are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, aryl, R²²,SR²⁰, NR²⁰R²³, NR²⁰COR²¹, NR²⁰CO₂R²¹, NR²⁰SO₂R²¹, OR²⁰, CN, CO₂R²⁰, andCONR²⁰R²³; R²⁰ is a member selected from the group consisting of H, C₁₋₂alkyl; R²¹ is a member selected from the group consisting of C₁₋₃ alkyl;R²² is a member selected from the group consisting of C₁₋₃ alkyl, aryl,which alkyl, aryl, are optionally substituted with 1 substituentindependently selected from halo, alkyl, mono- or dialkylamino, CN, CF₃;and R²³is R²¹ or H.
 19. The 2,6,9-trisubstituted purine composition ofclaim 12 wherein R₁′ is selected from the group consisting of aralkyl,pyridylalkyl, and substituted pyridylalkyl; R₂ is selected from thegroup consisting of alkyl, which alkyl is optionally substituted withfrom 1 to 2 substituents independently selected from the groupconsisting of halo, R²², and OR²⁰ ; R₄ and R₅ are each a substitutedalkyl having from 2 to 6 carbon atoms optionally substituted with from 1substituent independently selected from the group consisting of R²²,NR²⁰R²³, and OR²⁰; R²⁰ is a member selected from the group consisting ofH, C₁₋₂ alkyl R²¹ is a member selected from the group consisting of HC₁₋₃ alkyl; R²² is a member selected from the group consisting of C₁₋₃alkyl; and R²³ is R²¹ or H.
 20. The 2,6,9-trisubstituted purinecomposition of claim 12 wherein R₁′ is CH₂-aryl or CH₂-substituted aryl,R₂ is lower alkyl or substituted lower alkyl, and R₄ and R₅ are each—CH₂ CH₂OH , —CHR′CH₂OH, or —CH₂ CHR′OH wherein R′ is hydrogen or alkylhaving from 1 to 6 carbon atoms.
 21. The 2,6,9-trisubstituted purinecomposition of claim 12 wherein R₁′ is CH₂-Aryl or CH₂-substituted aryl,R₂ is lower alkyl, and R₄═H, and R₅ is —CH₂CH₂NH₂, CHR′CH₂NH₂,—CH₂CHR′NH₂ wherein R′ is hydrogen or alkyl having from 1 to 6 carbonatoms.
 22. The 2,6,9-trisubstituted purine composition of claim 21wherein R₂ is isopropyl.
 23. The 2,6,9-trisubstituted purine compositionof claim 12 wherein R₁′ is CH₂-Aryl or CH₂-substituted aryl, R₂ is loweralkyl, and R⁴═—CH₂CH₂OH R₅ is CH₂CH₂NH₂, or —CHR′CH₂NH₂, or —CH₂CHR′NH₂wherein R′ is hydrogen or alkyl having from 1 to 6 carbon atoms.
 24. The2,6,9-trisubstituted purine composition of claim 23 wherein R₂ isisopropyl.
 25. The 2,6,9-trisubstituted purine composition of claim 20wherein R₂ is isopropyl.
 26. The 2,6,9-trisubstituted purine compositionof claim 12 wherein R₁′ is selected from the group consisting of aryl,substituted aryl, pyridyl, and substituted pyridyl, R₂ is selected fromthe group consisting of lower alkyl, substituted lower alkyl, and alkylcycloalkyl, and R₄ and R₅ are each a substituted lower alkyl having from2 to 6 carbon atoms.
 27. The 2,6,9-trisubstituted purine composition ofclaim 12 wherein R₁′ is aryl or substituted aryl, R₂ is lower alkyl, orsubstituted lower alkyl, and R₄ and R₅ are each CH₂CH₂OH, —CHR′CH₂_(OH, or —CH) ₂CHR′OH wherein R′ is hydrogen or alkyl having from 1 to 6carbon atoms.
 28. The 2,6,9-trisubstituted purine composition of claim27 wherein R₂ is isopropyl.
 29. The 2,6,9-trisubstituted purinecomposition of claim 12 wherein R₁′ is benzyl substituted with ahalogen, alkoxy, phenyl, pyridyl or nitro group, R₂ is isopropyl, and R₄and R₅ are each —CH₂CH₂OH.
 30. The 2,6,9-trisubstuted purine compositionof claim 12 wherein R₁′ is benzyl substituted with a halogen, alkoxy,phenyl, pyridyl or nitro group, R₂ is isopropyl, R⁴ =H, andR₅═CH₂CH₂NH₂.
 31. The 2,6,9-trisubstuted purine composition of claim 12wherein R₁′ is benzyl substituted with a halogen, alkoxy, C₁₋₃ alkyl,CF₃, phenyl, pyridyl or nitro group, R₂ is isopropyl, R₄=H, andR₅=CH₂CHR′NH₂ wherein R′is hydrogen or alkyl having from 1 to 6 carbonatoms.
 32. The 2,6,9-trisubstuted purine composition of claim 12 whereinR₁′ is benzyl substituted with a halogen, alkoxy, C₁₋₃ alkyl, CF₃,phenyl, pyridyl or nitro group, R₂ is isopropyl, R₄=H, andR₅=CH₂CR′R′NH₂ wherein R′ is hydrogen or alkyl having from 1 to 6 carbonatoms.
 33. The 2,6,9-trisubstuted purine composition of claim 1 selectedfrom the group consisting of2-{(2-hydroxyethyl)[9-(methylethyl)-6-({[4-(trifluoromethyl)phenyl]methyl}amino)purin-2-yl]amino}ethan-1-ol,{((2S)oxolan-2-yl)methyl](6-{[(4-fluorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,[((2R)oxolan-2-yl)methyl](6-{[(4-fluorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,(2-aminoethyl)(6-{[3,5-dichlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,(2-aminoethyl)[6-({[4-chloro-3-(trifluoromethyl)phenyl]methyl}amino)-9-(methylethyl)purin-2-yl]amine,[-[(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]-3-methylbutanamide,(2-amino-2-methylpropyl)(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amine,3-(2-[bis(2-hydroxyethyl)amino]-6-{[4-chlorophenyl)methyl]amino}purin-9-yl)butan-2-one,2-[(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]-3-methylbutan-1-ol,4-[({2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}amino)methyl]benzenesulfonamide,2-[(2-hydroxyethyl)(6-{[(4-methoxyphenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]ethan-1-ol,2-((2-hydroxyethyl){9-(methylethyl)-6-[(4-phenylphenyl)amino]purin-2-yl}amino)ethan-1-ol,{2-[(2-amino-2-propyl)amino]-9-(methylethyl)purin-6-yl}[(4-hlorophenyl)methyl]amine,{2-[(2-aminoethyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]amine,{2-[(2-aminopropyl)amino]-9-(methylethyl)purin-6-yl}[(4-chlorophenyl)methyl]amineand2-[(2-aminoethyl)(6-{[(4-chlorophenyl)methyl]amino}-9-(methylethyl)purin-2-yl)amino]ethan-1-ol.34. The 2,6,9-trisubstituted purine composition of claim 12 wherein R₁′is phenyl substituted with a halogen, alkoxy, phenyl, pryidyl or nitrogroup, R₂ is isopropyl, and R₄ and R₅ are each —CH₂CH₂OH.
 35. The2,6,9-trisubstituted purine composition of claim 12 wherein R₁′ isbiphenylmethyl, R₂ is isopropyl, and R₄ and R₅ are each —CH₂CH₂OH. 36.The 2,6,9-trisubstituted purine composition of claim 12 wherein R₁′ isselected from the group consisting of 3-methylthiophenyl,4-methylthiophenyl, 4-phenylbenzyl, 4-methoxybenzyl, 4-biphenyl,3-methoxybenzyl, 4-(2-thienyl)benzyl, 4-(4-methyl)phenylbenzyl,4-(4-trifluoromethyl)phenylbenzyl, 4-(4-nitrilo)phenylbenzyl,4-(2-pyridinyl)benzyl, piperonyl, 3-methoxbenzyl, 4-chlorobenzyl, and4-nitrobenzyl, R₂ is isopropyl, and R₄ and R₅ are both CH₂CH₂OH.
 37. The2,6,9-trisubstituted purine composition of claim 36 wherein R₁′ isselected from the group of compounds consisting of 4-methoxybenzyl,4-phenylbenzyl, 4-methoxybenzyl, 4-biphenyl, 3-methoxybenzyl,4-(2-thienyl)benzyl, 4-(4-methyl)phenylbenzyl,4-(4-trifluoromethyl)phenylbenzyl, 4-(4-nitrilo)phenylbenzyl,4-(2-pyridinyl)benzyl, piperonyl, 3-thiomethoxphenyl,4-thiomethoxyphenyl and 4-bromophenyl.
 38. A cationic salt of thecomposition of claim
 1. 39. An acid addition salt of the composition ofclaim
 1. 40. A method for inhibiting cell proliferation in mammalscomprising administering a therapeutically effective amount of thecomposition of claim 1 to the mammal.
 41. The method of claim 40 whereinthe therapeutically effective amount ranges from about 0.001 to about100 mg/kg weight of the mammal.
 42. The method of claim 40 wherein thecomposition is administered to a mammal suffering from a cellproliferation disorder selected from the group consisting of rheumatoidarthritis, lupus, type I diabetes, multiple sclerosis, cancer,restenosis following ballon angioplasty or atherectomy, restenosisfollowing vascular modifying surgical procedures, host graft disease,and gout.
 43. The method of claim 42 wherein the cell proliferationdisorder is restenosis.
 44. The method of claim 42 wherein the cellproliferation is disorder cancer.
 45. The method of claim 42 wherein thecell proliferation disorder is polycystic kidney disease.
 46. The methodof claim 42 wherein the mammal is a human.
 47. A pharmaceuticalcomposition of matter comprising the composition of claim 1 and one ormore pharmaceutical excipients.
 48. An antifungal agent useful fortreating fingal infections in humans, and animals comprising thecomposition of claim
 1. 49. The method of claim 42 wherein the cellproliferation disorder is selected from the group consisting of lymphoydneoplasm, cancer of the colon, breast cancer, ovarian cancer, pancreaticcancer, and cancers derived from endothelial cells.